🔗

Mappings

MONDO

MONDO:0018881 myelodysplastic syndrome

Primary MONDO disease identifier anchoring the MDS disease-level mechanism graph.

NCIT

NCIT:C3247 Myelodysplastic Syndrome

NCIT provides the canonical oncology disease class for MDS and is paired routinely with MONDO for hematologic malignancy entries.

NCIT

NCIT:C3247 Myelodysplastic Syndrome

NCIT provides the canonical oncology disease class for MDS and is paired routinely with MONDO for hematologic malignancy entries.

◆

Subtypes

5

MDS with Ring Sideroblasts (SF3B1-mutant) NCIT:C198587

NCIT NCIT:C198587

Lower-risk MDS subtype defined by somatic SF3B1 mutation, ring sideroblasts, ineffective erythropoiesis, and a relatively indolent clinical course. Increasingly recognized as a distinct nosologic entity defined by founder genetics rather than morphology alone.

NCIT: Myelodysplastic Syndrome with Mutated SF3B1 (skos:exactMatch) NCIT:C198587

Show evidence (1 reference)

PMID:32347921 SUPPORT Human Clinical

"SF3B1 mutation identifies a condition characterized by ring sideroblasts (RS), ineffective erythropoiesis, and indolent clinical course."

Supports modeling SF3B1-mutant MDS with ring sideroblasts as a distinct, genetically defined lower-risk subtype.

MDS with Isolated del(5q) NCIT:C6867

NCIT NCIT:C6867

MDS subtype defined by an isolated interstitial deletion of the long arm of chromosome 5, characteristically presenting with macrocytic anemia and preserved or elevated platelet counts. The only MDS subtype historically defined by a cytogenetic abnormality and the canonical lenalidomide-responsive subtype.

NCIT: Myelodysplastic Syndrome with del(5q) (skos:exactMatch) NCIT:C6867

Show evidence (1 reference)

PMID:32347921 SUPPORT Human Clinical

"the myelodysplastic syndrome (MDS) with isolated del(5q) remains so far the only MDS subtype defined by a genetic abnormality."

Supports recognition of isolated del(5q) MDS as a distinct, genetically defined subtype.

MDS with Biallelic TP53 Inactivation NCIT:C200381

NCIT NCIT:C200381

High-risk MDS subtype defined by multi-hit (biallelic) TP53 inactivation, associated with complex karyotype, high-risk presentation, resistance to conventional therapy, and elevated risk of leukemic transformation. Distinct in outcome from monoallelic TP53-mutated MDS.

NCIT: Myelodysplastic Syndrome with Biallelic TP53 Mutation (skos:exactMatch) NCIT:C200381

Show evidence (1 reference)

PMID:32747829 SUPPORT Human Clinical

"Established associations with complex karyotype, few co-occurring mutations, high-risk presentation and poor outcomes were specific to multi-hit patients only."

Supports modeling biallelic (multi-hit) TP53 MDS as a distinct high-risk subtype separable from monoallelic TP53 disease.

MDS with Increased Blasts NCIT:C7506

NCIT NCIT:C7506

Higher-risk MDS subtype defined by an increased proportion of bone marrow or peripheral blood blasts (still below the 20% threshold that defines AML), carrying a substantial risk of progression to acute myeloid leukemia. This is the subtype population in which hypomethylating agents prolong survival.

NCIT: Myelodysplastic Syndrome with Excess Blasts (skos:exactMatch) NCIT:C7506

Show evidence (1 reference)

PMID:19230772 SUPPORT Human Clinical

"Patients with myelodysplastic syndromes who had intermediate-2 or high-risk scores on the international prognosis scoring system (known as higher-risk myelo-dysplastic syndromes) have a median survival of 1·2 years or 0·4 years, respectively,5 and a high-risk for progression to acute myeloid leukaemia."

Supports the higher-risk, increased-blast MDS category as a distinct prognostic group with high risk of AML transformation.

MDS with Low Blasts NCIT:C200389

NCIT NCIT:C200389

Lower-risk MDS category with bone marrow blasts below the increased-blast threshold, in which morbidity is driven primarily by cytopenias (especially anemia) and management focuses on supportive care and erythropoiesis-promoting therapy rather than leukemia prevention.

NCIT: Myelodysplastic Syndrome with Low Blasts (skos:exactMatch) NCIT:C200389

Show evidence (1 reference)

PMID:31914241 SUPPORT Human Clinical

"Luspatercept reduced the severity of anemia in patients with lower-risk myelodysplastic syndromes with ring sideroblasts"

Supports the lower-risk (low-blast) MDS population in which anemia and transfusion dependence, rather than blast excess, dominate management.

⚙

Pathophysiology

4

Clonal Hematopoietic Stem Cell Transformation

MDS originates in a hematopoietic stem cell that acquires recurrent somatic driver mutations, establishing a dominant clone in the bone marrow. Most patients carry one or more oncogenic mutations affecting RNA splicing, DNA methylation, chromatin regulation, transcription factors, or cell signaling.

hematopoietic stem cell CL:0000037

hematopoietic stem cell proliferation GO:0071425 ↑ INCREASED

bone marrow UBERON:0002371

Downstream

Spliceosome and Epigenetic Founder Lesions Clonal expansion is initiated and shaped by early founder mutations in splicing and epigenetic-regulator genes.

Show evidence (1 reference)

PMID:24030381 SUPPORT Human Clinical

"Seventy-eight percent of patients had 1 or more oncogenic mutations."

Supports MDS as a clonal stem cell disorder driven by recurrent somatic oncogenic mutations.

Spliceosome and Epigenetic Founder Lesions

Early driver mutations in the RNA splicing machinery (SF3B1, SRSF2, U2AF1, ZRSR2) and in DNA-methylation and chromatin regulators (TET2, DNMT3A, ASXL1, EZH2) establish the clonal architecture of MDS. Splicing-factor mutations are highly specific to myeloid neoplasms with dysplasia and frequently arise as the founder lesion, dictating subsequent disease trajectory.

hematopoietic stem cell CL:0000037

mRNA splicing, via spliceosome GO:0000398 ⚠ ABNORMAL chromatin organization GO:0006325 ⚠ ABNORMAL

Downstream

Ineffective Hematopoiesis and Cytopenias Aberrant splicing and dysregulated epigenetic programs compromise myeloid differentiation and maturation.

Show evidence (2 references)

PMID:21909114 SUPPORT Human Clinical

"most of the mutations, which occurred in a mutually exclusive manner, affected genes involved in the 3'-splice site recognition during pre-mRNA processing, inducing abnormal RNA splicing and compromised haematopoiesis."

Supports splicing-machinery mutations as recurrent, mutually exclusive founder lesions that produce abnormal splicing and impaired hematopoiesis.

PMID:24030381 SUPPORT Human Clinical

"early driver mutations, typically affecting genes involved in RNA splicing, dictate future trajectories of disease evolution with distinct clinical phenotypes."

Supports the model in which early splicing-gene founder mutations determine MDS disease evolution and clinical phenotype.

Ineffective Hematopoiesis and Cytopenias

Dysplastic clonal progenitors undergo accelerated intramedullary apoptosis and fail to mature normally, producing a paradox of hypercellular or normocellular marrow with peripheral blood cytopenias. Ineffective erythropoiesis is the dominant lesion in many lower-risk subtypes, manifesting as anemia.

erythroid lineage cell CL:0000764

erythrocyte differentiation GO:0030218 ↓ DECREASED apoptotic process GO:0006915 ↑ INCREASED

bone marrow UBERON:0002371

Downstream

Clonal Evolution and Leukemic Transformation Accumulating mutations and subclonal expansion drive progression toward acute myeloid leukemia in a subset of patients.

Show evidence (1 reference)

PMID:24030381 SUPPORT Human Clinical

"Myelodysplastic syndromes (MDS) are a heterogeneous group of chronic hematological malignancies characterized by dysplasia, ineffective hematopoiesis"

Supports dysplasia and ineffective hematopoiesis as the defining pathophysiologic features producing peripheral cytopenias.

Clonal Evolution and Leukemic Transformation

Acquisition of additional cooperating mutations and outgrowth of aggressive subclones drive progression of MDS to acute myeloid leukemia. Leukemia-free survival deteriorates progressively as the number of driver mutations increases, and the risk is greatest in higher-risk, increased-blast disease.

hematopoietic stem cell CL:0000037

myeloid cell differentiation GO:0030099 ↓ DECREASED

Show evidence (1 reference)

PMID:24030381 SUPPORT Human Clinical

"leukemia-free survival deteriorated steadily as numbers of driver mutations increased."

Supports progressive clonal evolution and increasing driver-mutation burden as the mechanism of leukemic transformation risk in MDS.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

5

Blood 4

Anemia Anemia HP:0001903

Show evidence (1 reference)

PMID:24030381 SUPPORT Human Clinical

"Myelodysplastic syndromes (MDS) are a heterogeneous group of chronic hematological malignancies characterized by dysplasia, ineffective hematopoiesis"

Ineffective hematopoiesis underlies the anemia that dominates the MDS clinical picture.

Thrombocytopenia Thrombocytopenia HP:0001873

Show evidence (1 reference)

PMID:36066514 SUPPORT Human Clinical

"clonal hematopoietic malignancies that cause morphologic bone marrow dysplasia along with anemia, neutropenia, or thrombocytopenia."

Thrombocytopenia is one of the defining peripheral cytopenias produced by ineffective hematopoiesis in MDS.

Neutropenia Decreased total neutrophil count HP:0001875

Show evidence (1 reference)

PMID:36066514 SUPPORT Human Clinical

"clonal hematopoietic malignancies that cause morphologic bone marrow dysplasia along with anemia, neutropenia, or thrombocytopenia."

Neutropenia is one of the defining peripheral cytopenias of MDS and underlies the increased infection risk in affected patients.

Myelodysplasia Myelodysplasia HP:0002863

Show evidence (1 reference)

PMID:24030381 SUPPORT Human Clinical

"Myelodysplastic syndromes (MDS) are a heterogeneous group of chronic hematological malignancies characterized by dysplasia, ineffective hematopoiesis"

Morphologic dysplasia is one of the two defining marrow features of MDS.

Other 1

Elevated Bone Marrow Ring Sideroblast Count Elevated bone marrow ring sideroblast count HP:0004864

Show evidence (1 reference)

PMID:32347921 SUPPORT Human Clinical

"SF3B1 mutation identifies a condition characterized by ring sideroblasts (RS), ineffective erythropoiesis, and indolent clinical course."

Ring sideroblasts are the defining morphologic feature of SF3B1-mutant MDS-RS.

🧬

Genetic Associations

7

SF3B1 (Recurrent somatic founder mutation in splicing factor gene)

Gene: SF3B1 hgnc:10768 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:32347921 SUPPORT Human Clinical

"Approximately half of MDS patients carry somatic mutations in spliceosome genes, with SF3B1 being the most commonly mutated one."

SF3B1 is the single most commonly mutated splicing-factor gene in MDS and defines the ring-sideroblast subtype.

SRSF2 (Recurrent somatic mutation in splicing factor gene)

Gene: SRSF2 hgnc:10783 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:21909114 SUPPORT Human Clinical

"novel pathway mutations involving multiple components of the RNA splicing machinery, including U2AF35, ZRSR2, SRSF2 and SF3B1."

SRSF2 is one of the core recurrently mutated spliceosome genes in MDS.

U2AF1 (Recurrent somatic mutation in splicing factor gene)

Gene: U2AF1 hgnc:12453 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:21909114 SUPPORT Human Clinical

"these splicing pathway mutations were frequent (∼45 to ∼85%) in, and highly specific to, myeloid neoplasms showing features of myelodysplasia."

U2AF1 (U2AF35) is among the recurrent, MDS-specific splicing-pathway mutations.

TET2 (Recurrent somatic mutation in epigenetic regulator gene)

Gene: TET2 hgnc:25941 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:24030381 SUPPORT Human Clinical

"Sequencing of MDS genomes has identified mutations in genes implicated in RNA splicing, DNA modification, chromatin regulation, and cell signaling."

TET2 is a recurrently mutated DNA-modification (epigenetic) gene in the MDS driver landscape.

DNMT3A (Recurrent somatic mutation in DNA methyltransferase gene)

Gene: DNMT3A hgnc:2978 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:21415852 SUPPORT Human Clinical

"we report the frequency of DNMT3A mutations in patients with de novo MDS, and their association with secondary AML."

DNMT3A is a recurrently mutated DNA-methyltransferase (epigenetic) founder gene in MDS, associated with worse survival and progression to AML.

ASXL1 (Recurrent somatic mutation in chromatin regulator gene)

Gene: ASXL1 hgnc:18318 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:24030381 SUPPORT Human Clinical

"Sequencing of MDS genomes has identified mutations in genes implicated in RNA splicing, DNA modification, chromatin regulation, and cell signaling."

ASXL1 is a recurrently mutated chromatin-regulation gene in MDS associated with adverse prognosis.

TP53 (Recurrent somatic mutation in tumor suppressor gene)

Gene: TP53 hgnc:11998 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:32747829 SUPPORT Human Clinical

"One-third of TP53-mutated patients had monoallelic mutations whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting."

TP53 allelic state stratifies MDS, with biallelic (multi-hit) inactivation defining a distinct high-risk subtype.

💊

Medical Actions

6

Supportive Care and Red Cell Transfusion

Action: supportive care MAXO:0000950

Best supportive care, including red-cell transfusions, iron chelation, and antimicrobial management of neutropenic infection, remains a foundation of MDS management, especially in lower-risk disease driven by anemia.

Azacitidine

Action: Pharmacotherapy NCIT:C15986

Agent: azacitidine CHEBI:2038

Azacitidine is a hypomethylating agent (DNA methyltransferase inhibitor) that prolongs overall survival and delays AML transformation in higher-risk MDS compared with conventional care regimens.

Show evidence (1 reference)

PMID:19230772 SUPPORT Human Clinical

"Treatment with azacitidine prolongs overall survival and lowers the risk of progression to acute myeloid leukaemia in patients with higher-risk myelodysplastic syndrome"

The AZA-001 phase III trial established that azacitidine prolongs survival and reduces AML progression in higher-risk MDS.

Decitabine

Action: Pharmacotherapy NCIT:C15986

Agent: decitabine CHEBI:50131

Decitabine (5-aza-2'-deoxycytidine) is a hypomethylating agent used in higher-risk MDS, reversing aberrant DNA methylation to restore myeloid differentiation.

Show evidence (1 reference)

PMID:16532500 SUPPORT Human Clinical

"Decitabine was found to be clinically effective in the treatment of patients with MDS, provided durable responses, and improved time to AML transformation or death."

This phase III randomized study established decitabine as an effective hypomethylating-agent therapy in MDS.

Lenalidomide

Action: Pharmacotherapy NCIT:C15986

Agent: lenalidomide CHEBI:63791

Lenalidomide reduces transfusion requirements and induces cytogenetic responses in MDS with isolated del(5q), suppressing the abnormal 5q- clone.

Show evidence (1 reference)

PMID:17021321 SUPPORT Human Clinical

"Lenalidomide can reduce transfusion requirements and reverse cytologic and cytogenetic abnormalities in patients who have the myelodysplastic syndrome with the 5q31 deletion."

The MDS-003 trial established lenalidomide as the targeted therapy for the del(5q) MDS subtype.

Luspatercept

Action: Pharmacotherapy NCIT:C15986

Agent: luspatercept NCIT:C104012

Luspatercept is a recombinant fusion protein (erythroid maturation agent) that reduces anemia and transfusion dependence in lower-risk MDS with ring sideroblasts refractory to erythropoiesis-stimulating agents.

Show evidence (1 reference)

PMID:31914241 SUPPORT Human Clinical

"Transfusion independence for 8 weeks or longer was observed in 38% of the patients in the luspatercept group, as compared with 13% of those in the placebo group"

The MEDALIST trial demonstrated luspatercept improves transfusion independence in lower-risk MDS with ring sideroblasts.

Allogeneic Hematopoietic Stem Cell Transplantation

Action: allogeneic hematopoietic stem cell transplantation MAXO:0001479

Allogeneic hematopoietic stem cell transplantation is the only potentially curative therapy for MDS, used primarily in eligible higher-risk patients.

{ }

Source YAML

click to show

name: Myelodysplastic Syndrome
creation_date: "2026-06-08T00:00:00Z"
description: >-
  Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal
  hematopoietic stem cell neoplasms characterized by ineffective hematopoiesis,
  morphologic dysplasia in one or more myeloid lineages, recurrent somatic
  mutations in RNA splicing, epigenetic, transcription-factor, and cell-signaling
  genes, peripheral blood cytopenias, and a variable risk of progression to acute
  myeloid leukemia. Subtypes are increasingly defined by founder genetics
  (e.g., SF3B1-mutant MDS with ring sideroblasts, MDS with isolated del(5q),
  MDS with biallelic TP53 inactivation) alongside blast percentage.
categories:
- Hematologic Malignancy
- Myeloid Neoplasm
synonyms:
- MDS
- myelodysplastic neoplasm
- myelodysplasia
parents:
- myeloid neoplasm
disease_term:
  preferred_term: myelodysplastic syndrome
  term:
    id: MONDO:0018881
    label: myelodysplastic syndrome
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0018881
      label: myelodysplastic syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      Primary MONDO disease identifier anchoring the MDS disease-level
      mechanism graph.
  ncit_mappings:
  - term:
      id: NCIT:C3247
      label: Myelodysplastic Syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: NCIT
    mapping_justification: >-
      NCIT provides the canonical oncology disease class for MDS and is
      paired routinely with MONDO for hematologic malignancy entries.
review_notes: >-
  Curated for issue #4016 (CURATE_ROOT_WITH_SUBTYPES). MDS is modeled as a
  single disease-level mechanism graph with WHO/ICC mutation-defined subtypes
  captured as has_subtypes facets (SF3B1/ring sideroblasts, isolated del(5q),
  biallelic TP53, increased blasts, low blasts). MDS is distinct from related
  myeloid neoplasms already in the knowledge base (Chronic Myelomonocytic
  Leukemia, Primary Myelofibrosis, the acute leukemias) — it is a clonal
  cytopenia/dysplasia entity below the 20% blast threshold for AML.
has_subtypes:
- name: MDS-RS/SF3B1
  display_name: MDS with Ring Sideroblasts (SF3B1-mutant)
  description: >-
    Lower-risk MDS subtype defined by somatic SF3B1 mutation, ring sideroblasts,
    ineffective erythropoiesis, and a relatively indolent clinical course.
    Increasingly recognized as a distinct nosologic entity defined by founder
    genetics rather than morphology alone.
  mappings:
    ncit_mappings:
    - term:
        id: NCIT:C198587
        label: Myelodysplastic Syndrome with Mutated SF3B1
      mapping_predicate: skos:exactMatch
      mapping_source: NCIT
      mapping_justification: >-
        NCIT provides the genetic-subtype label for SF3B1-mutant MDS.
  evidence:
  - reference: PMID:32347921
    reference_title: >-
      SF3B1-mutant MDS as a distinct disease subtype: a proposal from the
      International Working Group for the Prognosis of MDS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SF3B1
      mutation identifies a condition characterized by ring sideroblasts (RS),
      ineffective erythropoiesis, and indolent clinical course.
    explanation: >-
      Supports modeling SF3B1-mutant MDS with ring sideroblasts as a distinct,
      genetically defined lower-risk subtype.
- name: MDS-del(5q)
  display_name: MDS with Isolated del(5q)
  description: >-
    MDS subtype defined by an isolated interstitial deletion of the long arm of
    chromosome 5, characteristically presenting with macrocytic anemia and
    preserved or elevated platelet counts. The only MDS subtype historically
    defined by a cytogenetic abnormality and the canonical lenalidomide-responsive
    subtype.
  mappings:
    ncit_mappings:
    - term:
        id: NCIT:C6867
        label: Myelodysplastic Syndrome with del(5q)
      mapping_predicate: skos:exactMatch
      mapping_source: NCIT
      mapping_justification: >-
        NCIT provides the cytogenetic-subtype label for MDS with del(5q).
  evidence:
  - reference: PMID:32347921
    reference_title: >-
      SF3B1-mutant MDS as a distinct disease subtype: a proposal from the
      International Working Group for the Prognosis of MDS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the myelodysplastic syndrome
      (MDS) with isolated del(5q) remains so far the only MDS subtype defined by a
      genetic abnormality.
    explanation: >-
      Supports recognition of isolated del(5q) MDS as a distinct, genetically
      defined subtype.
- name: MDS-biTP53
  display_name: MDS with Biallelic TP53 Inactivation
  description: >-
    High-risk MDS subtype defined by multi-hit (biallelic) TP53 inactivation,
    associated with complex karyotype, high-risk presentation, resistance to
    conventional therapy, and elevated risk of leukemic transformation. Distinct
    in outcome from monoallelic TP53-mutated MDS.
  mappings:
    ncit_mappings:
    - term:
        id: NCIT:C200381
        label: Myelodysplastic Syndrome with Biallelic TP53 Mutation
      mapping_predicate: skos:exactMatch
      mapping_source: NCIT
      mapping_justification: >-
        NCIT provides the genetic-subtype label for biallelic TP53-mutated MDS.
  evidence:
  - reference: PMID:32747829
    reference_title: >-
      Implications of TP53 allelic state for genome stability, clinical
      presentation and outcomes in myelodysplastic syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Established
      associations with complex karyotype, few co-occurring mutations, high-risk
      presentation and poor outcomes were specific to multi-hit patients only.
    explanation: >-
      Supports modeling biallelic (multi-hit) TP53 MDS as a distinct high-risk
      subtype separable from monoallelic TP53 disease.
- name: MDS-IB
  display_name: MDS with Increased Blasts
  description: >-
    Higher-risk MDS subtype defined by an increased proportion of bone marrow
    or peripheral blood blasts (still below the 20% threshold that defines AML),
    carrying a substantial risk of progression to acute myeloid leukemia. This
    is the subtype population in which hypomethylating agents prolong survival.
  mappings:
    ncit_mappings:
    - term:
        id: NCIT:C7506
        label: Myelodysplastic Syndrome with Excess Blasts
      mapping_predicate: skos:exactMatch
      mapping_source: NCIT
      mapping_justification: >-
        NCIT "Myelodysplastic Syndrome with Excess Blasts" is the established
        oncology label for the increased-blast (higher-risk) MDS category.
  evidence:
  - reference: PMID:19230772
    reference_title: >-
      Efficacy of azacitidine compared with that of conventional care regimens
      in the treatment of higher-risk myelodysplastic syndromes: a randomised,
      open-label, phase III study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with myelodysplastic syndromes who had intermediate-2 or high-risk scores on the international prognosis scoring system (known as higher-risk myelo-dysplastic syndromes) have a median survival of 1·2 years or 0·4 years, respectively,5 and a high-risk for progression to acute myeloid leukaemia.
    explanation: >-
      Supports the higher-risk, increased-blast MDS category as a distinct
      prognostic group with high risk of AML transformation.
- name: MDS-LB
  display_name: MDS with Low Blasts
  description: >-
    Lower-risk MDS category with bone marrow blasts below the increased-blast
    threshold, in which morbidity is driven primarily by cytopenias
    (especially anemia) and management focuses on supportive care and
    erythropoiesis-promoting therapy rather than leukemia prevention.
  mappings:
    ncit_mappings:
    - term:
        id: NCIT:C200389
        label: Myelodysplastic Syndrome with Low Blasts
      mapping_predicate: skos:exactMatch
      mapping_source: NCIT
      mapping_justification: >-
        NCIT provides the WHO-2022/ICC-aligned label for the low-blast MDS
        category.
  evidence:
  - reference: PMID:31914241
    reference_title: "Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Luspatercept reduced the severity of anemia in patients with
      lower-risk myelodysplastic syndromes with ring sideroblasts
    explanation: >-
      Supports the lower-risk (low-blast) MDS population in which anemia and
      transfusion dependence, rather than blast excess, dominate management.
prevalence:
- population: General population, United States
  notes: >-
    The yearly incidence of MDS is approximately 4 per 100,000 people in the
    United States, rising sharply with age to roughly 25 per 100,000 in people
    aged 65 years and older. The median age at diagnosis is approximately 70
    years, and MDS is more common in men than women (about 5.4 vs 2.9 per
    100,000 per year).
  evidence:
  - reference: PMID:36066514
    reference_title: >-
      Diagnosis and Treatment of Myelodysplastic Syndromes: A Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The yearly
      incidence of MDS is approximately 4 per 100 000 people in the United States and
      is higher among patients with advanced age.
    explanation: >-
      Provides the population-level incidence and age dependence of MDS from a
      contemporary clinical review.
pathophysiology:
- name: Clonal Hematopoietic Stem Cell Transformation
  description: >-
    MDS originates in a hematopoietic stem cell that acquires recurrent somatic
    driver mutations, establishing a dominant clone in the bone marrow. Most
    patients carry one or more oncogenic mutations affecting RNA splicing, DNA
    methylation, chromatin regulation, transcription factors, or cell signaling.
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  locations:
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  biological_processes:
  - preferred_term: hematopoietic stem cell proliferation
    modifier: INCREASED
    term:
      id: GO:0071425
      label: hematopoietic stem cell proliferation
  downstream:
  - target: Spliceosome and Epigenetic Founder Lesions
    description: >-
      Clonal expansion is initiated and shaped by early founder mutations in
      splicing and epigenetic-regulator genes.
  evidence:
  - reference: PMID:24030381
    reference_title: >-
      Clinical and biological implications of driver mutations in myelodysplastic
      syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seventy-eight
      percent of patients had 1 or more oncogenic mutations.
    explanation: >-
      Supports MDS as a clonal stem cell disorder driven by recurrent somatic
      oncogenic mutations.
- name: Spliceosome and Epigenetic Founder Lesions
  description: >-
    Early driver mutations in the RNA splicing machinery (SF3B1, SRSF2, U2AF1,
    ZRSR2) and in DNA-methylation and chromatin regulators (TET2, DNMT3A, ASXL1,
    EZH2) establish the clonal architecture of MDS. Splicing-factor mutations
    are highly specific to myeloid neoplasms with dysplasia and frequently arise
    as the founder lesion, dictating subsequent disease trajectory.
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  biological_processes:
  - preferred_term: mRNA splicing, via spliceosome
    modifier: ABNORMAL
    term:
      id: GO:0000398
      label: mRNA splicing, via spliceosome
  - preferred_term: chromatin organization
    modifier: ABNORMAL
    term:
      id: GO:0006325
      label: chromatin organization
  downstream:
  - target: Ineffective Hematopoiesis and Cytopenias
    description: >-
      Aberrant splicing and dysregulated epigenetic programs compromise
      myeloid differentiation and maturation.
  evidence:
  - reference: PMID:21909114
    reference_title: >-
      Frequent pathway mutations of splicing machinery in myelodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      most of the mutations, which occurred in a mutually exclusive
      manner, affected genes involved in the 3'-splice site recognition during
      pre-mRNA processing, inducing abnormal RNA splicing and compromised
      haematopoiesis.
    explanation: >-
      Supports splicing-machinery mutations as recurrent, mutually exclusive
      founder lesions that produce abnormal splicing and impaired hematopoiesis.
  - reference: PMID:24030381
    reference_title: >-
      Clinical and biological implications of driver mutations in myelodysplastic
      syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      early driver mutations,
      typically affecting genes involved in RNA splicing, dictate future trajectories
      of disease evolution with distinct clinical phenotypes.
    explanation: >-
      Supports the model in which early splicing-gene founder mutations
      determine MDS disease evolution and clinical phenotype.
- name: Ineffective Hematopoiesis and Cytopenias
  description: >-
    Dysplastic clonal progenitors undergo accelerated intramedullary apoptosis
    and fail to mature normally, producing a paradox of hypercellular or
    normocellular marrow with peripheral blood cytopenias. Ineffective
    erythropoiesis is the dominant lesion in many lower-risk subtypes,
    manifesting as anemia.
  cell_types:
  - preferred_term: erythroid lineage cell
    term:
      id: CL:0000764
      label: erythroid lineage cell
  locations:
  - preferred_term: bone marrow
    term:
      id: UBERON:0002371
      label: bone marrow
  biological_processes:
  - preferred_term: erythrocyte differentiation
    modifier: DECREASED
    term:
      id: GO:0030218
      label: erythrocyte differentiation
  - preferred_term: apoptotic process
    modifier: INCREASED
    term:
      id: GO:0006915
      label: apoptotic process
  downstream:
  - target: Clonal Evolution and Leukemic Transformation
    description: >-
      Accumulating mutations and subclonal expansion drive progression toward
      acute myeloid leukemia in a subset of patients.
  evidence:
  - reference: PMID:24030381
    reference_title: >-
      Clinical and biological implications of driver mutations in myelodysplastic
      syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Myelodysplastic syndromes (MDS) are a heterogeneous group of chronic
      hematological malignancies characterized by dysplasia, ineffective hematopoiesis
    explanation: >-
      Supports dysplasia and ineffective hematopoiesis as the defining
      pathophysiologic features producing peripheral cytopenias.
- name: Clonal Evolution and Leukemic Transformation
  description: >-
    Acquisition of additional cooperating mutations and outgrowth of aggressive
    subclones drive progression of MDS to acute myeloid leukemia. Leukemia-free
    survival deteriorates progressively as the number of driver mutations
    increases, and the risk is greatest in higher-risk, increased-blast disease.
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  biological_processes:
  - preferred_term: myeloid cell differentiation
    modifier: DECREASED
    term:
      id: GO:0030099
      label: myeloid cell differentiation
  evidence:
  - reference: PMID:24030381
    reference_title: >-
      Clinical and biological implications of driver mutations in myelodysplastic
      syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      leukemia-free survival deteriorated steadily as numbers of driver mutations
      increased.
    explanation: >-
      Supports progressive clonal evolution and increasing driver-mutation burden
      as the mechanism of leukemic transformation risk in MDS.
phenotypes:
- name: Anemia
  category: Hematologic
  description: >-
    Reduced red cell mass from ineffective erythropoiesis is the most common
    presenting cytopenia in MDS, causing fatigue, pallor, and frequently
    transfusion dependence.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:24030381
    reference_title: >-
      Clinical and biological implications of driver mutations in myelodysplastic
      syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Myelodysplastic syndromes (MDS) are a heterogeneous group of chronic
      hematological malignancies characterized by dysplasia, ineffective hematopoiesis
    explanation: >-
      Ineffective hematopoiesis underlies the anemia that dominates the MDS
      clinical picture.
- name: Thrombocytopenia
  category: Hematologic
  description: >-
    Reduced platelet production from dysplastic megakaryopoiesis produces
    thrombocytopenia and an associated bleeding tendency in many MDS patients.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:36066514
    reference_title: >-
      Diagnosis and Treatment of Myelodysplastic Syndromes: A Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      clonal hematopoietic malignancies that cause morphologic bone
      marrow dysplasia along with anemia, neutropenia, or thrombocytopenia.
    explanation: >-
      Thrombocytopenia is one of the defining peripheral cytopenias produced by
      ineffective hematopoiesis in MDS.
- name: Neutropenia
  category: Hematologic
  description: >-
    Reduced neutrophil production predisposes MDS patients to recurrent and
    severe infections, a major source of morbidity and mortality.
  phenotype_term:
    preferred_term: Decreased neutrophil count
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  evidence:
  - reference: PMID:36066514
    reference_title: >-
      Diagnosis and Treatment of Myelodysplastic Syndromes: A Review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      clonal hematopoietic malignancies that cause morphologic bone
      marrow dysplasia along with anemia, neutropenia, or thrombocytopenia.
    explanation: >-
      Neutropenia is one of the defining peripheral cytopenias of MDS and
      underlies the increased infection risk in affected patients.
- name: Myelodysplasia
  category: Hematologic
  description: >-
    Morphologic dysplasia in one or more myeloid lineages (dyserythropoiesis,
    dysgranulopoiesis, dysmegakaryopoiesis) is the defining marrow finding of
    MDS.
  phenotype_term:
    preferred_term: Myelodysplasia
    term:
      id: HP:0002863
      label: Myelodysplasia
  evidence:
  - reference: PMID:24030381
    reference_title: >-
      Clinical and biological implications of driver mutations in myelodysplastic
      syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Myelodysplastic syndromes (MDS) are a heterogeneous group of chronic
      hematological malignancies characterized by dysplasia, ineffective hematopoiesis
    explanation: >-
      Morphologic dysplasia is one of the two defining marrow features of MDS.
- name: Elevated Bone Marrow Ring Sideroblast Count
  category: Hematologic
  subtype: MDS-RS/SF3B1
  description: >-
    Iron-laden mitochondria forming a perinuclear ring in erythroblasts (ring
    sideroblasts) characterize SF3B1-mutant MDS with ring sideroblasts.
  phenotype_term:
    preferred_term: Elevated bone marrow ring sideroblast count
    term:
      id: HP:0004864
      label: Elevated bone marrow ring sideroblast count
  evidence:
  - reference: PMID:32347921
    reference_title: >-
      SF3B1-mutant MDS as a distinct disease subtype: a proposal from the
      International Working Group for the Prognosis of MDS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SF3B1
      mutation identifies a condition characterized by ring sideroblasts (RS),
      ineffective erythropoiesis, and indolent clinical course.
    explanation: >-
      Ring sideroblasts are the defining morphologic feature of SF3B1-mutant
      MDS-RS.
genetic:
- name: SF3B1
  association: Recurrent somatic founder mutation in splicing factor gene
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: SF3B1
    term:
      id: hgnc:10768
      label: SF3B1
  evidence:
  - reference: PMID:32347921
    reference_title: >-
      SF3B1-mutant MDS as a distinct disease subtype: a proposal from the
      International Working Group for the Prognosis of MDS.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Approximately half of MDS patients carry somatic mutations
      in spliceosome genes, with SF3B1 being the most commonly mutated one.
    explanation: >-
      SF3B1 is the single most commonly mutated splicing-factor gene in MDS and
      defines the ring-sideroblast subtype.
  notes: >-
    SF3B1 mutation defines a distinct lower-risk MDS subtype with ring
    sideroblasts and relatively favorable prognosis.
- name: SRSF2
  association: Recurrent somatic mutation in splicing factor gene
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: SRSF2
    term:
      id: hgnc:10783
      label: SRSF2
  evidence:
  - reference: PMID:21909114
    reference_title: >-
      Frequent pathway mutations of splicing machinery in myelodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      novel pathway mutations involving multiple components of the RNA
      splicing machinery, including U2AF35, ZRSR2, SRSF2 and SF3B1.
    explanation: >-
      SRSF2 is one of the core recurrently mutated spliceosome genes in MDS.
- name: U2AF1
  association: Recurrent somatic mutation in splicing factor gene
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: U2AF1
    term:
      id: hgnc:12453
      label: U2AF1
  evidence:
  - reference: PMID:21909114
    reference_title: >-
      Frequent pathway mutations of splicing machinery in myelodysplasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      these splicing pathway mutations were frequent (∼45 to ∼85%) in, and
      highly specific to, myeloid neoplasms showing features of myelodysplasia.
    explanation: >-
      U2AF1 (U2AF35) is among the recurrent, MDS-specific splicing-pathway
      mutations.
- name: TET2
  association: Recurrent somatic mutation in epigenetic regulator gene
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: TET2
    term:
      id: hgnc:25941
      label: TET2
  evidence:
  - reference: PMID:24030381
    reference_title: >-
      Clinical and biological implications of driver mutations in myelodysplastic
      syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequencing of MDS
      genomes has identified mutations in genes implicated in RNA splicing, DNA
      modification, chromatin regulation, and cell signaling.
    explanation: >-
      TET2 is a recurrently mutated DNA-modification (epigenetic) gene in the
      MDS driver landscape.
  notes: >-
    TET2 is an epigenetic-regulator founder lesion frequently mutated in MDS and
    clonal hematopoiesis.
- name: DNMT3A
  association: Recurrent somatic mutation in DNA methyltransferase gene
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: DNMT3A
    term:
      id: hgnc:2978
      label: DNMT3A
  evidence:
  - reference: PMID:21415852
    reference_title: >-
      Recurrent DNMT3A mutations in patients with myelodysplastic syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we report the frequency of DNMT3A mutations in patients with de novo MDS,
      and their association with secondary AML.
    explanation: >-
      DNMT3A is a recurrently mutated DNA-methyltransferase (epigenetic) founder
      gene in MDS, associated with worse survival and progression to AML.
  notes: >-
    DNMT3A mutations occur early in MDS and confer worse overall survival and
    more rapid progression to acute myeloid leukemia.
- name: ASXL1
  association: Recurrent somatic mutation in chromatin regulator gene
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: ASXL1
    term:
      id: hgnc:18318
      label: ASXL1
  evidence:
  - reference: PMID:24030381
    reference_title: >-
      Clinical and biological implications of driver mutations in myelodysplastic
      syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequencing of MDS
      genomes has identified mutations in genes implicated in RNA splicing, DNA
      modification, chromatin regulation, and cell signaling.
    explanation: >-
      ASXL1 is a recurrently mutated chromatin-regulation gene in MDS associated
      with adverse prognosis.
- name: TP53
  association: Recurrent somatic mutation in tumor suppressor gene
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  gene_term:
    preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
  evidence:
  - reference: PMID:32747829
    reference_title: >-
      Implications of TP53 allelic state for genome stability, clinical
      presentation and outcomes in myelodysplastic syndromes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One-third of TP53-mutated patients had monoallelic mutations whereas two-thirds
      had multiple hits (multi-hit) consistent with biallelic targeting.
    explanation: >-
      TP53 allelic state stratifies MDS, with biallelic (multi-hit) inactivation
      defining a distinct high-risk subtype.
  notes: >-
    Biallelic (multi-hit) TP53 inactivation, not monoallelic mutation, drives
    the high-risk complex-karyotype TP53 MDS subtype.
treatments:
- name: Supportive Care and Red Cell Transfusion
  description: >-
    Best supportive care, including red-cell transfusions, iron chelation, and
    antimicrobial management of neutropenic infection, remains a foundation of
    MDS management, especially in lower-risk disease driven by anemia.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
- name: Azacitidine
  description: >-
    Azacitidine is a hypomethylating agent (DNA methyltransferase inhibitor)
    that prolongs overall survival and delays AML transformation in higher-risk
    MDS compared with conventional care regimens.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: azacitidine
      term:
        id: CHEBI:2038
        label: 5-azacytidine
  evidence:
  - reference: PMID:19230772
    reference_title: >-
      Efficacy of azacitidine compared with that of conventional care regimens
      in the treatment of higher-risk myelodysplastic syndromes: a randomised,
      open-label, phase III study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment with azacitidine prolongs overall survival and lowers the risk of progression to acute myeloid leukaemia in patients with higher-risk myelodysplastic syndrome
    explanation: >-
      The AZA-001 phase III trial established that azacitidine prolongs survival
      and reduces AML progression in higher-risk MDS.
- name: Decitabine
  description: >-
    Decitabine (5-aza-2'-deoxycytidine) is a hypomethylating agent used in
    higher-risk MDS, reversing aberrant DNA methylation to restore myeloid
    differentiation.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: decitabine
      term:
        id: CHEBI:50131
        label: 5-aza-2'-deoxycytidine
  evidence:
  - reference: PMID:16532500
    reference_title: >-
      Decitabine improves patient outcomes in myelodysplastic syndromes: results
      of a phase III randomized study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Decitabine was found to be clinically effective in the treatment of
      patients with MDS, provided durable responses, and improved time to AML
      transformation or death.
    explanation: >-
      This phase III randomized study established decitabine as an effective
      hypomethylating-agent therapy in MDS.
- name: Lenalidomide
  description: >-
    Lenalidomide reduces transfusion requirements and induces cytogenetic
    responses in MDS with isolated del(5q), suppressing the abnormal 5q- clone.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: lenalidomide
      term:
        id: CHEBI:63791
        label: lenalidomide
  evidence:
  - reference: PMID:17021321
    reference_title: >-
      Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lenalidomide can reduce transfusion requirements and reverse
      cytologic and cytogenetic abnormalities in patients who have the myelodysplastic
      syndrome with the 5q31 deletion.
    explanation: >-
      The MDS-003 trial established lenalidomide as the targeted therapy for the
      del(5q) MDS subtype.
- name: Luspatercept
  description: >-
    Luspatercept is a recombinant fusion protein (erythroid maturation agent)
    that reduces anemia and transfusion dependence in lower-risk MDS with ring
    sideroblasts refractory to erythropoiesis-stimulating agents.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: luspatercept
      term:
        id: NCIT:C104012
        label: Luspatercept
  evidence:
  - reference: PMID:31914241
    reference_title: "Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Transfusion independence for 8 weeks or longer was
      observed in 38% of the patients in the luspatercept group, as compared with 13%
      of those in the placebo group
    explanation: >-
      The MEDALIST trial demonstrated luspatercept improves transfusion
      independence in lower-risk MDS with ring sideroblasts.
- name: Allogeneic Hematopoietic Stem Cell Transplantation
  description: >-
    Allogeneic hematopoietic stem cell transplantation is the only potentially
    curative therapy for MDS, used primarily in eligible higher-risk patients.
  treatment_term:
    preferred_term: allogeneic hematopoietic stem cell transplantation
    term:
      id: MAXO:0001479
      label: allogeneic hematopoietic stem cell transplantation

📚

References & Deep Research

Deep Research

1

Falcon ▸

Myelodysplastic Syndrome (Myelodysplastic Neoplasms, MDS): Disease Characteristics Research Report

Edison Scientific Literature 59 citations 2026-06-08T11:22:18.720072

Myelodysplastic Syndrome (Myelodysplastic Neoplasms, MDS): Disease Characteristics Research Report

Target Disease

Disease name: Myelodysplastic Syndrome (WHO 2022 preferred: Myelodysplastic Neoplasms, abbreviated MDS) (lucero2023managementofpatients pages 1-2)
Category: Clonal hematopoietic stem/progenitor cell myeloid neoplasm / bone marrow failure malignancy with variable risk of AML transformation (niscola2024latestinsightsand pages 1-2, thalla2025advancesandchallenges pages 1-2)
ICD-10 (clinical coding commonly used): D46 (captured in GBD analyses covering ICD-10 D45–D47 and noted in MDS burden methods) (gou2025globalregionaland pages 2-3)
MONDO / MeSH / Orphanet / OMIM IDs: Not directly retrievable with tool-backed evidence in this run; use external ontology sources to finalize identifiers.

1. Disease Information

1.1 Concise overview (current understanding)

MDS are heterogeneous clonal myeloid malignancies arising from hematopoietic stem cells, characterized by morphologic dysplasia, ineffective hematopoiesis, and resulting peripheral blood cytopenias with a variable propensity to progress to acute myeloid leukemia (AML) (thalla2025advancesandchallenges pages 1-2, lucero2023managementofpatients pages 1-2).

1.2 Common synonyms / alternative names

Myelodysplastic syndromes (historical term) (lucero2023managementofpatients pages 1-2)
Myelodysplastic neoplasms (WHO 2022 nomenclature) (lucero2023managementofpatients pages 1-2)
“Preleukemic” bone marrow failure disorder (conceptual; progression risk emphasized in multiple reviews) (thalla2025advancesandchallenges pages 1-2)

1.3 Aggregated resources vs individual patients

The information below is derived from aggregated disease-level resources (reviews, registries, large cohorts, and randomized trials) rather than EHR-only case series (e.g., GBD analyses; registry-based classification validations; phase 3 trials) (zhang2022comparisonofthe pages 1-2, platzbecker2023…andsafety pages 1-2, gou2025globalregionaland pages 1-2).

2. Etiology

2.1 Disease causal factors (mechanistic, genetic, environmental)

MDS arises via multistep acquisition of somatic genetic lesions in hematopoietic stem/progenitor cells, producing clonal dominance, dysplasia, and marrow failure; the process is influenced by aging, immune/inflammatory microenvironmental changes, and selection pressures including genotoxic exposures (niscola2024latestinsightsand pages 1-2, karel2024myelodysplasticneoplasms(mds) pages 1-2, nachtkamp2023myelodysplasticsyndromesnew pages 1-2).

2.2 Risk factors

2.2.1 Age and premalignant clonal states

MDS commonly arises from antecedent clonal hematopoiesis states including CHIP and CCUS, which are detectable via genomic analysis and represent premalignant conditions in some individuals (niscola2024latestinsightsand pages 1-2).
CHIP prevalence rises with age (≈10% by age ≥80 in one review), and CHIP confers an estimated ~0.5–1% per year risk of developing MDS (nachtkamp2023myelodysplasticsyndromesnew pages 1-2).

2.2.2 Therapy-related and genotoxic exposures

Prior exposure to chemotherapy, radiotherapy, and radioiodine therapy is explicitly highlighted as an MDS risk factor in a 2023 clinical review (nachtkamp2023myelodysplasticsyndromesnew pages 1-2).
In clonal hematopoiesis literature, selection pressures promoting CH expansion and therapy-related myeloid neoplasms include chemotherapy agents (e.g., cisplatin, etoposide, doxorubicin) and radiation (zhang2024implicationsofclonal pages 2-4).

2.2.3 Smoking

Smoking is discussed as a selection pressure in CH biology and is associated with specific mutation patterns (e.g., association with ASXL1 mutations) (zhang2024implicationsofclonal pages 2-4).

2.2.4 Autoimmune/inflammatory comorbidity

Pre-existing autoimmune disease is reported in ~10–30% of MDS patients, and inflammatory pathway activation is implicated in pathogenesis (niscola2024latestinsightsand pages 1-2).

2.2.5 Germline predisposition

Germline predisposition is described as more frequent than previously recognized, particularly in younger adults (nachtkamp2023myelodysplasticsyndromesnew pages 1-2).

2.3 Protective factors

No tool-retrieved primary evidence identified specific protective genetic variants or environmental protective factors for MDS in this run.

2.4 Gene–environment interactions

Gene–environment interactions are framed largely through clonal selection: genotoxic therapy/radiation and smoking can preferentially expand clones with certain mutations (e.g., TP53, PPM1D), increasing risk of therapy-related myeloid neoplasms (zhang2024implicationsofclonal pages 2-4).

3. Phenotypes

3.1 Core clinical phenotype (symptoms/signs)

MDS clinical hallmarks include persistent cytopenias and marrow dysplasia due to ineffective hematopoiesis, typically manifesting as: - Anemia → fatigue, transfusion dependence - Neutropenia → infection susceptibility - Thrombocytopenia → bleeding/bruising These are described as the clinical consequences of ineffective hematopoiesis and cytopenias (niscola2024latestinsightsand pages 1-2).

3.2 Phenotype characteristics

Typical onset: largely older adults (median diagnosis around ~70–75 years in clinical reviews) (nachtkamp2023myelodysplasticsyndromesnew pages 1-2, thalla2025advancesandchallenges pages 1-2)
Severity/progression: variable; risk of AML progression depends on blast percentage, cytogenetics, and molecular profile (niscola2024latestinsightsand pages 6-7, hoff2023moleculardriversof pages 5-7)

3.3 Suggested HPO terms (examples)

(These are ontology suggestions; verify exact term IDs in HPO.) - Anemia; fatigue; dyspnea on exertion (symptom-level) - Neutropenia; recurrent infections - Thrombocytopenia; easy bruising; mucosal bleeding - Pancytopenia - Bone marrow dysplasia / ineffective hematopoiesis Supported as common cytopenic manifestations of MDS pathobiology (niscola2024latestinsightsand pages 1-2, thalla2025advancesandchallenges pages 1-2).

3.4 Quality-of-life impact

Transfusion dependence and chronic cytopenias reduce quality of life; transfusion dependence is described as being associated with reduced QoL metrics and inferior outcomes (stempel2025advancesandchallenges pages 5-7).

4. Genetic / Molecular Information

4.1 Common somatic mutation classes (current landscape)

Recurrent mutations span multiple biological programs (examples): - Epigenetic regulators: TET2, DNMT3A, ASXL1, EZH2, IDH1/2 (niscola2024latestinsightsand pages 1-2, hoff2023moleculardriversof pages 10-11) - Spliceosome: SF3B1, SRSF2, U2AF1, ZRSR2 (niscola2024latestinsightsand pages 1-2, hoff2023moleculardriversof pages 10-11) - Transcription factors / tumor suppressor: TP53, RUNX1, BCOR (niscola2024latestinsightsand pages 1-2, hoff2023moleculardriversof pages 10-11) - Cohesin complex: STAG2 (hoff2023moleculardriversof pages 10-11) - Signaling genes: NRAS/KRAS, JAK2, CBL (niscola2024latestinsightsand pages 1-2, hoff2023moleculardriversof pages 10-11)

At least one somatic mutation is reported in >90% of MDS patients (niscola2024latestinsightsand pages 6-7).

4.2 Quantitative mutation frequencies (selected examples)

ASXL1 ~15–20% in MDS (hoff2023moleculardriversof pages 10-11)
EZH2 ~5–10% (hoff2023moleculardriversof pages 10-11)
TP53 ~10% de novo; higher in therapy-related disease (25%) and in del(5q) disease (20%); multi-hit TP53 predicts worse OS and AML transformation (hoff2023moleculardriversof pages 10-11)

4.3 Cytogenetic abnormalities

Common lesions include del(5q), monosomy/deletion 7, del(20q), trisomy 8, and complex karyotype (niscola2024latestinsightsand pages 1-2, karel2024myelodysplasticneoplasms(mds) pages 1-2).

4.4 Epigenetic information

MDS biology is strongly influenced by epigenetic dysregulation (DNA methylation and histone modifications), reflected by frequent mutations in epigenetic regulators (DNMT3A/TET2/ASXL1/EZH2) (niscola2024latestinsightsand pages 1-2, hoff2023moleculardriversof pages 10-11).

4.5 Suggested gene/protein ontologies (examples)

GO biological processes (suggestions): hematopoiesis; myeloid cell differentiation; RNA splicing; DNA methylation; chromatin organization; inflammatory response.
CL cell types (suggestions): hematopoietic stem cell; myeloid progenitor cell; erythroid progenitor; megakaryocyte.

5. Environmental Information

5.1 Environmental/lifestyle contributors

Evidence in retrieved sources supports: - Smoking as a modifiable exposure linked to clonal hematopoiesis patterns and highlighted as an addressable risk factor in burden discussions (gou2025globalregionaland pages 16-18, zhang2024implicationsofclonal pages 2-4).

5.2 Prior medical exposures

Prior chemotherapy and radiation therapy are repeatedly flagged as risk-enhancing and are core to therapy-related myeloid neoplasms (nachtkamp2023myelodysplasticsyndromesnew pages 1-2, zhang2024implicationsofclonal pages 2-4).

5.3 Infectious agents

No evidence in retrieved sources supports a specific infectious etiology for MDS.

6. Mechanism / Pathophysiology

6.1 High-level causal chain (trigger → cellular effects → clinical phenotype)

Aging and/or genotoxic exposures (chemo/radiation; smoking; chronic inflammation) promote acquisition/selection of somatic mutations in HSCs (nachtkamp2023myelodysplasticsyndromesnew pages 1-2, zhang2024implicationsofclonal pages 2-4).
Emergence of clonal hematopoiesis (CHIP) and intermediate states such as CCUS (CHIP + persistent cytopenia), with increased risk of progression to myeloid neoplasia (testa2025clonalhematopoiesisa pages 16-18, niscola2024latestinsightsand pages 1-2).
Expansion of mutant clones with defects in differentiation/survival pathways produces ineffective hematopoiesis and dysplasia, causing persistent cytopenias (niscola2024latestinsightsand pages 1-2).
Accumulation of additional lesions (e.g., TP53 multi-hit, complex karyotype, signaling mutations) increases blasts and promotes progression to higher-risk MDS/AML (hoff2023moleculardriversof pages 10-11, hoff2023moleculardriversof pages 5-7).

6.2 Immune/inflammatory microenvironment

The marrow microenvironment is described as immune/inflammatory dysregulated, with inflammatory pathway activation contributing to clonal selection and suppression of normal hematopoiesis (niscola2024latestinsightsand pages 1-2). Mechanistically, inflammatory cytokines (e.g., TNFα, IL-6) can promote apoptosis of healthy progenitors and advantage MDS clones (baumann2025inflammatorysignalingin pages 5-7).

6.3 Molecular pathways and cellular processes (examples)

RNA splicing dysregulation (SF3B1/SRSF2/U2AF1/ZRSR2) (niscola2024latestinsightsand pages 1-2)
Epigenetic dysregulation (DNMT3A/TET2/ASXL1/EZH2; PRC2 biology) (hoff2023moleculardriversof pages 10-11)
DNA damage response selection (TP53; therapy-related evolution) (zhang2024implicationsofclonal pages 2-4)

7. Anatomical Structures Affected

7.1 Organ/tissue level

Primary site: bone marrow (hematopoietic tissue) with resulting peripheral blood cytopenias (niscola2024latestinsightsand pages 1-2, thalla2025advancesandchallenges pages 1-2)

7.2 Cell populations (suggestions)

Hematopoietic stem and progenitor cells (HSPCs)
Myeloid/erythroid/megakaryocytic lineages Supported by disease definition (HSC origin; multilineage dysplasia) (niscola2024latestinsightsand pages 1-2, thalla2025advancesandchallenges pages 1-2).

7.3 UBERON suggestions

Bone marrow (UBERON term suggested; verify ID externally)

8. Temporal Development

8.1 Onset pattern

Typically insidious/chronic, diagnosed during evaluation of cytopenias, predominantly in older adults (nachtkamp2023myelodysplasticsyndromesnew pages 1-2).

8.2 Progression and staging

Progression risk is tied to blast burden, cytogenetics, and molecular lesions; WHO/ICC provide blast-based increased-blast categories and ICC introduces an MDS/AML transitional group (hoff2023moleculardriversof pages 2-4, lucero2023managementofpatients pages 1-2).

9. Inheritance and Population

9.1 Epidemiology

Incidence: ~4 per 100,000 persons/year reported in a clinical review (nachtkamp2023myelodysplasticsyndromesnew pages 1-2); another review reports ~4 per 100,000 overall and ~25 per 100,000 among those ≥65 (thalla2025advancesandchallenges pages 1-2).
Median age: ~70–75 years (nachtkamp2023myelodysplasticsyndromesnew pages 1-2).
Median survival: ~3 years (nachtkamp2023myelodysplasticsyndromesnew pages 1-2).

9.2 Global burden (GBD 2021-based)

A GBD analysis combining MDS/MPN reported global incidence increasing from 171,132 (1990) to 341,017 (2021) with projected incidence ~457,320 by 2045 (gou2025globalregionaland pages 1-2).

9.3 Sex/age distribution

Burden is described as higher in men and concentrated in older ages in the GBD analysis (gou2025globalregionaland pages 1-2).

9.4 Germline predisposition

Germline predisposition appears more frequent than previously appreciated, especially in younger adults (nachtkamp2023myelodysplasticsyndromesnew pages 1-2).

10. Diagnostics

10.1 Standard diagnostic workup (current practice)

Gold standard: peripheral blood and bone marrow cytomorphology plus cytogenetics and molecular testing (nachtkamp2023myelodysplasticsyndromesnew pages 1-2).
Reviews emphasize diagnosis by cytomorphology supplemented by banding cytogenetics, histomorphology, and somatic mutation analyses (nachtkamp2023myelodysplasticsyndromesnew pages 1-2).

10.2 WHO 2022 / ICC 2022 classification diagnostics (key points)

WHO 2022/WHO-HAEM5 emphasizes genetically defined subtypes (e.g., SF3B1-mutant, biallelic TP53), retains dysplasia threshold (10%), and uses blast categories MDS-LB and MDS-IB (lucero2023managementofpatients pages 1-2, hoff2023moleculardriversof pages 2-4). ICC provides an alternative framework including an MDS/AML category for 10–19% blasts (hoff2023moleculardriversof pages 2-4, lucero2023managementofpatients pages 1-2).

Framework	Entity/category	BM blasts	PB blasts	Key defining features/notes	Primary citation id
WHO 2022 / WHO-HAEM5	MDS-LB	<5%	<2%	Low-blast MDS; morphologic category; dysplasia threshold remains 10% in any lineage; WHO groups MDS into genetically defined and morphologically defined entities. (hoff2023moleculardriversof pages 2-4, lucero2023managementofpatients pages 1-2)	(hoff2023moleculardriversof pages 2-4)
WHO 2022 / WHO-HAEM5	MDS-h	<5%	<2%	Hypoplastic MDS recognized as distinct subtype; bone marrow cellularity <25%. (hoff2023moleculardriversof pages 2-4, lee2024comparisonofthe pages 1-2)	(hoff2023moleculardriversof pages 2-4)
WHO 2022 / WHO-HAEM5	MDS-IB1	5-9%	2-9%	Replaces older MDS-EB1 terminology; 10% blast cutoff distinguishes IB1 from IB2. (hoff2023moleculardriversof pages 2-4, lucero2023managementofpatients pages 1-2, lapadat2025navigatingthenew pages 2-4)	(hoff2023moleculardriversof pages 2-4)
WHO 2022 / WHO-HAEM5	MDS-IB2	10-19%	5-19%	Includes Auer rods; WHO retains 20% blast cutoff separating MDS from AML. (hoff2023moleculardriversof pages 2-4, niscola2024latestinsightsand pages 4-6)	(hoff2023moleculardriversof pages 2-4)
WHO 2022 / WHO-HAEM5	AML cutoff	≥20%	≥20%	WHO retains classic 20% blast threshold for AML in MDS blast-based categories, although AML-defining lesions can supersede blast counting in some contexts. (niscola2024latestinsightsand pages 4-6, lee2024comparisonofthe pages 1-2)	(niscola2024latestinsightsand pages 4-6)
ICC 2022	MDS, NOS / low-blast equivalents	<5%	usually <2%	ICC retains MDS categories with 10% dysplasia threshold; also accepts certain MDS-defining cytogenetic/genetic lesions even without dysplasia in persistent cytopenia. (lucero2023managementofpatients pages 1-2)	(lucero2023managementofpatients pages 1-2)
ICC 2022	MDS with excess blasts (MDS-EB)	≥5%	≥2%	ICC uses MDS-EB terminology; prior WHO MDS-EB2 concept split, with 10-19% blasts moved to MDS/AML. (niscola2024latestinsightsand pages 4-6, lucero2023managementofpatients pages 1-2)	(niscola2024latestinsightsand pages 4-6)
ICC 2022	MDS/AML	10-19%	10-19% or corresponding increased blasts	Transitional category replacing prior MDS-EB2 for cases without AML-defining genetic lesions; emphasizes MDS-AML continuum. (hoff2023moleculardriversof pages 2-4, lee2024comparisonofthe pages 1-2, lapadat2025navigatingthenew pages 2-4)	(hoff2023moleculardriversof pages 2-4)
ICC 2022	AML threshold for recurrent genetic abnormalities	≥10% for most recurrent genetic abnormalities	≥10% for most recurrent genetic abnormalities	ICC requires 10% blasts to define AML with recurrent genetic abnormalities, except BCR::ABL1 and TP53-related exceptions noted in comparative review. (lee2024comparisonofthe pages 1-2)	(lee2024comparisonofthe pages 1-2)
WHO 2022 / ICC 2022	MDS-defining lesion: del(5q)	N/A	N/A	Recognized MDS-defining cytogenetic abnormality; isolated del(5q) remains a distinct entity/subtype; thrombocytosis can be present. (lucero2023managementofpatients pages 1-2, zhang2022comparisonofthe pages 1-2)	(lucero2023managementofpatients pages 1-2)
WHO 2022 / ICC 2022	MDS-defining lesion: multi-hit / biallelic TP53	N/A	N/A	Distinct high-risk entity in WHO (MDS-biTP53) and disease-defining lesion in ICC; associated with poor survival. (hoff2023moleculardriversof pages 2-4, zhang2022comparisonofthe pages 1-2)	(hoff2023moleculardriversof pages 2-4)
WHO 2022 / ICC 2022	MDS-defining lesion: -7 / del(7q)	N/A	N/A	Listed among cytogenetic lesions that can define MDS in persistent cytopenia, even without morphologic dysplasia in ICC framework. (lucero2023managementofpatients pages 1-2, karel2024myelodysplasticneoplasms(mds) pages 1-2)	(lucero2023managementofpatients pages 1-2)
WHO 2022 / ICC 2022	MDS-defining lesion: complex karyotype	N/A	N/A	Adverse cytogenetic category; ICC examples define complex karyotype as >3 unrelated clonal chromosomal abnormalities. (lucero2023managementofpatients pages 1-2)	(lucero2023managementofpatients pages 1-2)
ICC 2022 definition detail	Multi-hit TP53 definition	N/A	N/A	Multi-hit TP53 may be defined by: two distinct TP53 mutations each with VAF ≥10%; or one TP53 mutation plus 17p deletion; or TP53 mutation with VAF ≥50%; or TP53 mutation with copy-neutral LOH at 17p. (hoff2023moleculardriversof pages 2-4, abdulbaki2024abriefoverview pages 3-4)	(hoff2023moleculardriversof pages 2-4)

Table: This table compactly aligns WHO 2022/WHO-HAEM5 and ICC 2022 blast-based MDS categories and lists key MDS-defining cytogenetic/genetic lesions. It is useful for quickly comparing category names, blast cutoffs, and the operational definition of multi-hit TP53 used in contemporary classification.

10.3 Flow cytometry

Multiparameter flow cytometry is described as a complementary diagnostic tool; it is not mandated by international baseline guidelines but is “almost universally adopted” in practice for suspected cytopenias and dysplasia detection across marrow lineages, and can support follow-up/MRD assessment (verigou2024immunophenotypingmyelodysplasticneoplasms pages 1-2).

10.4 Molecular diagnostics / genome sequencing

Modern classifications incorporate genomic profiling to define entities (e.g., SF3B1-mutant, TP53-mutant MDS) and inform prognosis via IPSS-M; this is emphasized in a 2024 Haematologica review on genome sequencing in MDS management (cazzola2024genomesequencingin pages 1-3).

10.5 Differential diagnosis (high-level)

Key differentials include CHIP/CCUS, aplastic anemia, MDS/MPN overlap entities (e.g., CMML), and AML; ICC/WHO frameworks refine boundaries and integrate genetic criteria (hoff2023moleculardriversof pages 2-4, testa2025clonalhematopoiesisa pages 16-18).

11. Outcome / Prognosis

11.1 Natural history and AML transformation

Progression to acute leukemia occurs in ~25% in one clinical review (nachtkamp2023myelodysplasticsyndromesnew pages 1-2).
Another review states 30–40% progress to AML with poor post-transformation survival (death within ~4–6 months after transformation) (thalla2025advancesandchallenges pages 1-2).

11.2 Risk-stratified survival (IPSS-R)

Median overall survival by IPSS-R group (years): 8.8 (very low), 5.3 (low), 3.0 (intermediate), 1.6 (high), 0.8 (very high) (niscola2024latestinsightsand pages 6-7).

11.3 IPSS-M (molecular prognostication)

IPSS-M integrates clinical parameters, cytogenetics, and mutations (31 genes) and can reclassify a substantial fraction of patients (e.g., 42.5% reclassified; 29.3% upstaged in one external validation cohort) (nachtkamp2023myelodysplasticsyndromesnew pages 1-2, lee2024comparisonofthe pages 1-2).

11.4 High-risk genetic subgroup example

WHO 2022 MDS-biTP53 has markedly poor survival (median ~10 months in a reclassification study) (zhang2022comparisonofthe pages 1-2).

12. Treatment

12.1 Treatment goals (risk-adapted)

Lower-risk MDS: reduce cytopenia burden (especially anemia), decrease transfusion dependence, improve QoL (lucero2023managementofpatients pages 1-2, stempel2025advancesandchallenges pages 5-7).
Higher-risk MDS: prolong survival, prevent AML transformation, and pursue cure when feasible (HSCT) (kroger2024treatmentofhighrisk pages 1-2, nachtkamp2023myelodysplasticsyndromesnew pages 1-2).

12.2 Supportive and rehabilitative care (real-world implementations)

RBC transfusions are common (about half of patients require transfusions at diagnosis) and filtered products are recommended to reduce alloimmunization (kroger2024treatmentofhighrisk pages 1-2).
Iron chelation: recommended after heavy transfusion exposure; one review suggests iron chelation after >20 RBC units and ferritin >2500 ng/mL with goal ferritin <1000 ng/mL (stempel2025advancesandchallenges pages 5-7); another emphasizes early deferasirox use to prevent iron overload and improve outcomes (niscola2024latestinsightsand pages 8-10).

MAXO suggestions: blood transfusion; iron chelation therapy.

12.3 ESAs (erythropoiesis-stimulating agents)

ESA recommendation example: erythropoietin alfa for patients with endogenous EPO <200 ng/mL (nachtkamp2023myelodysplasticsyndromesnew pages 1-2).
Another review indicates practice use of ESA when EPO ≤500 mU/mL and alternatives when EPO >500 mU/mL (stempel2025advancesandchallenges pages 4-5).

MAXO suggestion: erythropoiesis-stimulating agent therapy.

12.4 Lenalidomide for del(5q) MDS

Lenalidomide is indicated for 5q deletion (nachtkamp2023myelodysplasticsyndromesnew pages 1-2).
Reported efficacy: phase II—76% reduced transfusions and 67% achieved transfusion independence; phase III—RBC-TI 61% (10 mg) and 51.1% (5 mg) vs 7.8% placebo, with AML-free survival benefit (stempel2025advancesandchallenges pages 4-5).

MAXO suggestion: lenalidomide therapy.

12.5 Luspatercept (TGF-β superfamily ligand trap)

Phase 3 COMMANDS (2023 interim analysis; ESA-naive, transfusion-dependent LR-MDS, sEPO <500 U/L): - Primary endpoint: RBC transfusion independence ≥12 weeks plus mean Hb increase ≥1.5 g/dL during weeks 1–24. - Interim efficacy set: 86/147 (59%) luspatercept vs 48/154 (31%) epoetin alfa; risk difference 26.6% (95% CI 15.8–37.4), p<0.0001 (platzbecker2023…andsafety pages 1-2). - Longer follow-up analyses report durable benefit including ≥1 year RBC-TI 44.5% vs 27.6% (p=0.0003) (garciamanero2025longtermtransfusionindependence pages 1-2).

MAXO suggestion: luspatercept therapy.

12.6 Imetelstat (telomerase inhibitor)

IMerge phase 3 (lower-risk transfusion-dependent non-del(5q) MDS): - Primary endpoint: RBC transfusion independence ≥8 weeks. - 40% imetelstat vs 15% placebo achieved ≥8-week TI (merz2024treatmentoflowerrisk pages 3-4, fahim2024imetelstatforanemia pages 2-3). - Sustained TI ≥1 year reported 18% vs 2% (p=0.023) (fahim2024imetelstatforanemia pages 2-3). - Key grade 3/4 toxicities include neutropenia and thrombocytopenia (e.g., 68% and 62% vs 3% and 8% placebo) (fahim2024imetelstatforanemia pages 2-3).

MAXO suggestion: imetelstat therapy.

12.7 Hypomethylating agents (HMAs) and higher-risk MDS

For higher-risk MDS patients not transplant-eligible, HMAs remain standard-of-care; azacitidine is described as the only approved non-transplant option in a 2024 Haematologica review (kroger2024treatmentofhighrisk pages 1-2).
Azacitidine improves outcomes in higher-risk non-transplant candidates per a 2023 clinical review (nachtkamp2023myelodysplasticsyndromesnew pages 1-2).

MAXO suggestions: azacitidine therapy; decitabine therapy.

12.8 Allogeneic hematopoietic stem cell transplantation (allo-HSCT)

Allo-HSCT is repeatedly emphasized as the only curative therapy for eligible patients, with relapse being a major cause of transplant failure (kroger2024treatmentofhighrisk pages 1-2, nachtkamp2023myelodysplasticsyndromesnew pages 1-2).

MAXO suggestion: allogeneic hematopoietic stem cell transplantation.

12.9 Targeted therapy example: IDH1 mutation (ivosidenib)

IDH1/2 mutations occur in ~5% of MDS (stempel2025advancesandchallenges pages 13-15). In IDH1-mutant MDS, ivosidenib is approved for relapsed/refractory disease with reported CR rates near 40% and median OS 35.7 months (AG120-C-001) (stempel2025advancesandchallenges pages 13-15).

MAXO suggestion: targeted small-molecule inhibitor therapy (IDH1 inhibitor).

13. Prevention

13.1 Primary prevention (risk factor modification)

Avoidance/minimization of unnecessary genotoxic exposure (chemotherapy/radiation when alternatives exist) is conceptually supported by the association between prior cytotoxic exposure and therapy-related myeloid neoplasms and shortened time to t-MN in CH carriers (zhang2024implicationsofclonal pages 2-4, nachtkamp2023myelodysplasticsyndromesnew pages 1-2).
Smoking cessation is supported as an addressable risk factor in burden discussions and is linked to clonal hematopoiesis selection patterns (gou2025globalregionaland pages 16-18, zhang2024implicationsofclonal pages 2-4).

13.2 Secondary prevention (early detection)

Emerging concept: monitoring high-risk CH/CCUS carriers for progression, since CH progression risk to malignancy is non-zero and measurable (e.g., ~4% over 8 years in one CH study cited in a review) (zhang2024implicationsofclonal pages 2-4). Practical implementation and validated screening programs are not established in the retrieved evidence.

13.3 Tertiary prevention

Supportive care (transfusions, iron chelation, infection management) to reduce complications of chronic cytopenias (kroger2024treatmentofhighrisk pages 1-2, stempel2025advancesandchallenges pages 5-7).

14. Other Species / Natural Disease

No tool-retrieved evidence in this run identified naturally occurring, veterinary-relevant MDS analogs with strong translational mapping.

15. Model Organisms / Experimental Systems

15.1 Human xenografts and humanized mice (current implementations)

A 2025 review summarizes that classical immunodeficient NSG/BRG mice support human HSC engraftment but poorly support myeloid/erythroid/megakaryocytic differentiation, motivating cytokine-humanized strains (munteanu2025humanizedmousemodels pages 2-3).

Key platforms: - NSG: good engraftment but limited myeloid differentiation (munteanu2025humanizedmousemodels pages 2-3). - MISTRG (human M-CSF, IL-3, GM-CSF, SIRPα, TPO): improved myeloid engraftment (>80% CD33+ reported) while preserving patient mutations (munteanu2025humanizedmousemodels pages 2-3). - NSG-SGM3 / NOG-EXL / NOGW-EXL / MISTRG6kitW41 (M6k): cytokine- and niche-engineered approaches improving lineage output and engraftment; NSG-SGM3 can have graft exhaustion and loss by ~24 weeks (munteanu2025humanizedmousemodels pages 7-7, munteanu2025humanizedmousemodels pages 5-7). - PDX models preserve genetic/phenotypic heterogeneity and can maintain mutations such as SF3B1, DNMT3A, SRSF2, TET2, TP53, RUNX1, KIT; engraftment often needs preconditioning (irradiation or macrophage depletion) and remains challenging for low-risk MDS (munteanu2025humanizedmousemodels pages 7-7, munteanu2025humanizedmousemodels pages 5-7).

15.2 Genetically engineered mouse models (GEMMs)

Examples recapitulating MDS-like features: - Runx1 deletion: anemia, trilineage dysplasia and rapid progression (munteanu2025humanizedmousemodels pages 5-7). - U2af1S34F knock-in: impaired hematopoiesis, mild dysplasia, splicing defects (munteanu2025humanizedmousemodels pages 5-7). - Ezh2 conditional knockout: impaired differentiation, dysplasia, leukemic progression (munteanu2025humanizedmousemodels pages 5-7).

15.3 Limitations (expert analysis)

No current murine model fully recapitulates the human marrow microenvironment and immune system; humanized models have limitations in long-term stability and modeling early/low-risk disease (munteanu2025humanizedmousemodels pages 1-2, munteanu2025humanizedmousemodels pages 8-10).

Expert opinions / analysis (authoritative themes)

Across contemporary reviews, expert consensus emphasizes: - Risk-adapted management integrating molecular profiling (IPSS-M, WHO/ICC genetically defined entities) (cazzola2024genomesequencingin pages 1-3, stempel2025advancesandchallenges pages 15-16). - Persistent clinical need for durable disease-modifying therapies, particularly for high-risk genomics (e.g., multi-hit TP53) where outcomes remain poor (stempel2025advancesandchallenges pages 13-15, zhang2022comparisonofthe pages 1-2). - Pragmatic multimodality diagnostics: morphology remains essential but is subjective; genomic and cytogenetic data increasingly define entities; flow cytometry is widely used as a complement (vicente2024whoiccclassificationfor pages 1-2, verigou2024immunophenotypingmyelodysplasticneoplasms pages 1-2).

Key recent developments (prioritized 2023–2024)

Classification modernization: WHO 2022/WHO-HAEM5 and ICC 2022 incorporate genetically defined entities (SF3B1-mutant, biallelic TP53) and refine blast-based categories (hoff2023moleculardriversof pages 2-4, lucero2023managementofpatients pages 1-2).
Frontline anemia therapy shift (2023): COMMANDS showed luspatercept superiority over epoetin alfa for a composite transfusion/Hb endpoint in ESA-naive LR-MDS (platzbecker2023…andsafety pages 1-2, merz2024treatmentoflowerrisk pages 3-4).
Molecular diagnostics and precision medicine (2024): genome sequencing reviews emphasize molecular taxonomy and IPSS-M integration into decision-making (cazzola2024genomesequencingin pages 1-3).

Notes on citation requirements (PMID limitation)

Many retrieved sources are journal articles with DOIs but PMIDs were not available in the extracted tool evidence; therefore, this report cites the retrieved sources via tool citation IDs, and provides URLs/DOIs (embedded in the evidence metadata). For a production knowledge base, PMIDs should be added by cross-referencing these DOIs in PubMed.

References

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(baumann2025inflammatorysignalingin pages 5-7): Artemis Margrith Baumann and Jana Maria Ellegast. Inflammatory signaling in the pathogenesis of acute myeloid leukemia. HemaSphere, Aug 2025. URL: https://doi.org/10.1002/hem3.70188, doi:10.1002/hem3.70188. This article has 6 citations and is from a peer-reviewed journal.
(hoff2023moleculardriversof pages 2-4): Fieke W. Hoff and Yazan F. Madanat. Molecular drivers of myelodysplastic neoplasms (mds)—classification and prognostic relevance. Cells, 12:627, Feb 2023. URL: https://doi.org/10.3390/cells12040627, doi:10.3390/cells12040627. This article has 16 citations.
(lee2024comparisonofthe pages 1-2): Wan-Hsuan Lee, Chien-Chin Lin, Cheng-Hong Tsai, Feng-Ming Tien, Min-Yen Lo, Mei-Hsuan Tseng, Yuan-Yeh Kuo, Shan-Chi Yu, Ming-Chih Liu, Chang-Tsu Yuan, Yi-Tsung Yang, Ming-Kai Chuang, Bor-Sheng Ko, Jih-Luh Tang, Hsun-I Sun, Yi-Kuang Chuang, Hwei-Fang Tien, Hsin-An Hou, and Wen-Chien Chou. Comparison of the 2022 world health organization classification and international consensus classification in myelodysplastic syndromes/neoplasms. Blood Cancer Journal, Apr 2024. URL: https://doi.org/10.1038/s41408-024-01031-9, doi:10.1038/s41408-024-01031-9. This article has 33 citations and is from a domain leading peer-reviewed journal.
(lapadat2025navigatingthenew pages 2-4): Mihai-Emilian Lapadat, Oana Stanca, Nicoleta Mariana Berbec, Cristina Negotei, and Andrei Colita. Navigating the new era in myelodysplastic neoplasms: a review of prognostic implications of the ipss-m score and 2022 who classification. Hematology Reports, 17:58, Oct 2025. URL: https://doi.org/10.3390/hematolrep17060058, doi:10.3390/hematolrep17060058. This article has 3 citations.
(niscola2024latestinsightsand pages 4-6): Pasquale Niscola, Valentina Gianfelici, Marco Giovannini, Daniela Piccioni, Carla Mazzone, and Paolo de Fabritiis. Latest insights and therapeutic advances in myelodysplastic neoplasms. Cancers, 16:1563, Apr 2024. URL: https://doi.org/10.3390/cancers16081563, doi:10.3390/cancers16081563. This article has 13 citations.
(abdulbaki2024abriefoverview pages 3-4): Rami Abdulbaki and Sheeja T. Pullarkat. A brief overview of the molecular landscape of myelodysplastic neoplasms. Current Oncology, 31:2353-2363, Apr 2024. URL: https://doi.org/10.3390/curroncol31050175, doi:10.3390/curroncol31050175. This article has 8 citations.
(verigou2024immunophenotypingmyelodysplasticneoplasms pages 1-2): Evgenia Verigou, Theodora Chatzilygeroudi, Vasileios Lazaris, Anne-Lise de Lastic, and Argiris Symeonidis. Immunophenotyping myelodysplastic neoplasms: the role of flow cytometry in the molecular classification era. Frontiers in Oncology, Oct 2024. URL: https://doi.org/10.3389/fonc.2024.1447001, doi:10.3389/fonc.2024.1447001. This article has 10 citations.
(cazzola2024genomesequencingin pages 1-3): Mario Cazzola and Luca Malcovati. Genome sequencing in the management of myelodysplastic syndromes and related disorders. Haematologica, 110:312-329, Oct 2024. URL: https://doi.org/10.3324/haematol.2023.284947, doi:10.3324/haematol.2023.284947. This article has 13 citations.
(kroger2024treatmentofhighrisk pages 1-2): Nicolaus Kröger. Treatment of high-risk myelodysplastic syndromes. Haematologica, 110:339-349, Dec 2024. URL: https://doi.org/10.3324/haematol.2023.284946, doi:10.3324/haematol.2023.284946. This article has 39 citations.
(niscola2024latestinsightsand pages 8-10): Pasquale Niscola, Valentina Gianfelici, Marco Giovannini, Daniela Piccioni, Carla Mazzone, and Paolo de Fabritiis. Latest insights and therapeutic advances in myelodysplastic neoplasms. Cancers, 16:1563, Apr 2024. URL: https://doi.org/10.3390/cancers16081563, doi:10.3390/cancers16081563. This article has 13 citations.
(stempel2025advancesandchallenges pages 4-5): J. Stempel, Tariq Kewan, and A. Zeidan. Advances and challenges in the management of myelodysplastic syndromes. Cancers, Jul 2025. URL: https://doi.org/10.3390/cancers17152469, doi:10.3390/cancers17152469. This article has 6 citations.
(garciamanero2025longtermtransfusionindependence pages 1-2): Guillermo Garcia-Manero, Valeria Santini, Amer M. Zeidan, Rami S. Komrokji, Veronika Pozharskaya, Shelonitda Rose, Karen Keeperman, Yinzhi Lai, Sameer Kalsekar, Barkha Aggarwal, Dimana Miteva, David Valcárcel, Pierre Fenaux, Jake Shortt, Matteo Giovanni Della Porta, and Uwe Platzbecker. Long-term transfusion independence with luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, lower-risk myelodysplastic syndromes in the commands trial. Advances in Therapy, 42:3576-3589, May 2025. URL: https://doi.org/10.1007/s12325-025-03208-5, doi:10.1007/s12325-025-03208-5. This article has 8 citations and is from a peer-reviewed journal.
(merz2024treatmentoflowerrisk pages 3-4): Almuth Maria Anni Merz and Uwe Platzbecker. Treatment of lower-risk myelodysplastic syndromes. Haematologica, 110:330-338, Oct 2024. URL: https://doi.org/10.3324/haematol.2023.284945, doi:10.3324/haematol.2023.284945. This article has 17 citations.
(fahim2024imetelstatforanemia pages 2-3): Shahariar Mohammed Fahim, Jeffrey A. Tice, Linda Luu, Josh J. Carlson, Marina Richardson, Belen Herce-Hagiwara, Ronald Dickerson, and Daniel A. Ollendorf. Imetelstat for anemia in lower-risk myelodysplastic syndromes: a summary from the institute for clinical and economic review's california technology assessment forum. Journal of managed care & specialty pharmacy, 30 12:1479-1485, Dec 2024. URL: https://doi.org/10.18553/jmcp.2024.30.12.1479, doi:10.18553/jmcp.2024.30.12.1479. This article has 0 citations.
(stempel2025advancesandchallenges pages 13-15): J. Stempel, Tariq Kewan, and A. Zeidan. Advances and challenges in the management of myelodysplastic syndromes. Cancers, Jul 2025. URL: https://doi.org/10.3390/cancers17152469, doi:10.3390/cancers17152469. This article has 6 citations.
(munteanu2025humanizedmousemodels pages 2-3): R. Munteanu, Diana Gulei, C. Moldovan, Emanuele Azzoni, Laura Belver, Richard-Ionut Feder, Simina Pîrv, A. Buzoianu, Hermann Einsele, Moshe Mittelman, Gabriel Ghiaur, Robert P Hasserjian, and C. Tomuleasa. Humanized mouse models in mds. Cell Death & Disease, Jul 2025. URL: https://doi.org/10.1038/s41419-025-07861-0, doi:10.1038/s41419-025-07861-0. This article has 4 citations and is from a peer-reviewed journal.
(munteanu2025humanizedmousemodels pages 7-7): R. Munteanu, Diana Gulei, C. Moldovan, Emanuele Azzoni, Laura Belver, Richard-Ionut Feder, Simina Pîrv, A. Buzoianu, Hermann Einsele, Moshe Mittelman, Gabriel Ghiaur, Robert P Hasserjian, and C. Tomuleasa. Humanized mouse models in mds. Cell Death & Disease, Jul 2025. URL: https://doi.org/10.1038/s41419-025-07861-0, doi:10.1038/s41419-025-07861-0. This article has 4 citations and is from a peer-reviewed journal.
(munteanu2025humanizedmousemodels pages 5-7): R. Munteanu, Diana Gulei, C. Moldovan, Emanuele Azzoni, Laura Belver, Richard-Ionut Feder, Simina Pîrv, A. Buzoianu, Hermann Einsele, Moshe Mittelman, Gabriel Ghiaur, Robert P Hasserjian, and C. Tomuleasa. Humanized mouse models in mds. Cell Death & Disease, Jul 2025. URL: https://doi.org/10.1038/s41419-025-07861-0, doi:10.1038/s41419-025-07861-0. This article has 4 citations and is from a peer-reviewed journal.
(munteanu2025humanizedmousemodels pages 1-2): R. Munteanu, Diana Gulei, C. Moldovan, Emanuele Azzoni, Laura Belver, Richard-Ionut Feder, Simina Pîrv, A. Buzoianu, Hermann Einsele, Moshe Mittelman, Gabriel Ghiaur, Robert P Hasserjian, and C. Tomuleasa. Humanized mouse models in mds. Cell Death & Disease, Jul 2025. URL: https://doi.org/10.1038/s41419-025-07861-0, doi:10.1038/s41419-025-07861-0. This article has 4 citations and is from a peer-reviewed journal.
(munteanu2025humanizedmousemodels pages 8-10): R. Munteanu, Diana Gulei, C. Moldovan, Emanuele Azzoni, Laura Belver, Richard-Ionut Feder, Simina Pîrv, A. Buzoianu, Hermann Einsele, Moshe Mittelman, Gabriel Ghiaur, Robert P Hasserjian, and C. Tomuleasa. Humanized mouse models in mds. Cell Death & Disease, Jul 2025. URL: https://doi.org/10.1038/s41419-025-07861-0, doi:10.1038/s41419-025-07861-0. This article has 4 citations and is from a peer-reviewed journal.
(stempel2025advancesandchallenges pages 15-16): J. Stempel, Tariq Kewan, and A. Zeidan. Advances and challenges in the management of myelodysplastic syndromes. Cancers, Jul 2025. URL: https://doi.org/10.3390/cancers17152469, doi:10.3390/cancers17152469. This article has 6 citations.
(vicente2024whoiccclassificationfor pages 1-2): Ana Isabel Vicente, Irene Luna, Juan Carlos Ruiz, María José Remigia, Andrés Jerez, Rafael Lluch, Inmaculada Llopis, María Josefa Marco, Carmen Benet, Carmen Alonso, María Dolores Linares, Luis Serrano, María Teresa Orero, Francisco José Ortuño, and María Leonor Senent. Who/icc classification for myelodysplastic neoplasms/syndromes performs better for subtype cytomorphological diagnosis? Diagnostics, 14:1631, Jul 2024. URL: https://doi.org/10.3390/diagnostics14151631, doi:10.3390/diagnostics14151631. This article has 2 citations.

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Myelodysplastic Syndrome (Myelodysplastic Neoplasms, MDS): Disease Characteristics Research Report

Target Disease

1. Disease Information

1.1 Concise overview (current understanding)

1.2 Common synonyms / alternative names

1.3 Aggregated resources vs individual patients

2. Etiology

2.1 Disease causal factors (mechanistic, genetic, environmental)

2.2 Risk factors

2.2.1 Age and premalignant clonal states

2.2.2 Therapy-related and genotoxic exposures

2.2.3 Smoking

2.2.4 Autoimmune/inflammatory comorbidity

2.2.5 Germline predisposition

2.3 Protective factors

2.4 Gene–environment interactions

3. Phenotypes

3.1 Core clinical phenotype (symptoms/signs)

3.2 Phenotype characteristics

3.3 Suggested HPO terms (examples)

3.4 Quality-of-life impact

4. Genetic / Molecular Information

4.1 Common somatic mutation classes (current landscape)

4.2 Quantitative mutation frequencies (selected examples)

4.3 Cytogenetic abnormalities

4.4 Epigenetic information

4.5 Suggested gene/protein ontologies (examples)

5. Environmental Information

5.1 Environmental/lifestyle contributors

5.2 Prior medical exposures

5.3 Infectious agents

6. Mechanism / Pathophysiology

6.1 High-level causal chain (trigger → cellular effects → clinical phenotype)

6.2 Immune/inflammatory microenvironment

6.3 Molecular pathways and cellular processes (examples)

7. Anatomical Structures Affected

7.1 Organ/tissue level

7.2 Cell populations (suggestions)

7.3 UBERON suggestions

8. Temporal Development

8.1 Onset pattern

8.2 Progression and staging

9. Inheritance and Population

9.1 Epidemiology

9.2 Global burden (GBD 2021-based)

9.3 Sex/age distribution

9.4 Germline predisposition

10. Diagnostics

10.1 Standard diagnostic workup (current practice)

10.2 WHO 2022 / ICC 2022 classification diagnostics (key points)

10.3 Flow cytometry

10.4 Molecular diagnostics / genome sequencing

10.5 Differential diagnosis (high-level)

11. Outcome / Prognosis

11.1 Natural history and AML transformation

11.2 Risk-stratified survival (IPSS-R)

11.3 IPSS-M (molecular prognostication)

11.4 High-risk genetic subgroup example

12. Treatment

12.1 Treatment goals (risk-adapted)

12.2 Supportive and rehabilitative care (real-world implementations)

12.3 ESAs (erythropoiesis-stimulating agents)

12.4 Lenalidomide for del(5q) MDS

12.5 Luspatercept (TGF-β superfamily ligand trap)

12.6 Imetelstat (telomerase inhibitor)

12.7 Hypomethylating agents (HMAs) and higher-risk MDS

12.8 Allogeneic hematopoietic stem cell transplantation (allo-HSCT)

12.9 Targeted therapy example: IDH1 mutation (ivosidenib)