Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Chronic Myelomonocytic Leukemia. Core disease mechanisms, molecular and ce...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] Low JAK2 V617F Allele Burden in Ph-Negative Chronic Myeloproliferative Neoplasms Is Associated with Additional CALR or MPL Gene Mutations

• Authors: T. Makarik, A. Abdullaev, E. Nikulina, S. Treglazova, E. Stepanova et al.
• Year: 2021
• Venue: Genes
• URL: https://www.semanticscholar.org/paper/38da3532577a45feeb5bf88726ce671d9565e8f0
• DOI: 10.3390/genes12040559
• PMID: 33921387
• PMCID: 8069892
• Citations: 6
• Influential citations: 2
• Summary: In cases of detecting MPNs with a low allelic load JAK2 V617F, it may be advisable to search for other molecular markers, primarily mutations in exon 9 of CALR, primarily to indicate that, at least in some cases, these mutations could be represented by different clones of malignant cells.
• Evidence snippets:
• Snippet 1 (score: 0.469) > Ph-negative myeloproliferative neoplasms (MPNs) arise as a result of the transformation of the hematopoietic stem cell, which leads to the aberrant clonal hematopoiesis and hyperplasia of the cells of the myeloid lineage [1]. The WHO (World Health Organization) classification of myeloid malignancies includes the following MPNs: Chronic myeloid leukemia (CML), chronic neutrophilic leukemia, polycythemia vera (PV), primary myelofibrosis (PMF), essential thrombocythemia (ET), chronic eosinophilic leukemia, and others, unclassified MPNs-U. These diseases are characterized by the hyperplasia of the myeloid cell lineages, thrombocytosis, splenomegaly, frequent thrombotic complications, with a long course-the risk of transformation to myelodysplastic syndrome and acute leukemia. Classical diagnosis, risk stratification, clinical characterization, and prognosis in patients with MPNs were based on histological analysis of bone marrow and peripheral blood. To date, it is known that the molecular mechanisms of MPN development are associated with hyperactivation of tyrosine kinases or with abnormalities of cytokine receptors. The beginning of deciphering these mechanisms started with the identification of the pathogenetic role of the chimeric BCR/ABL oncogene in chronic myeloid leukemia (CML), which arises as a result of reciprocal t(9:22) translocation forming the so-called Philadelphia chromosome [2,3]. The abnormal tyrosine kinase activity of the BCR/ABL protein leads to the dysregulation of many intracellular signaling pathways [4,5]. > In 2005, a point mutation in exon 14 of the JAK2 kinase gene was found in patients with MPNs, in which the amino acid valine was replaced by phenylalanine at position 617 (mutation JAK2 V617F) in the JH2 pseudokinase domain of the JAK2 protein [6][7][8][9].

[2] FAS/FASL gene polymorphisms in Turkish patients with chronic myeloproliferative disorders

• Authors: F. Ozdemirkiran, S. Nalbantoğlu, Z. Gokgoz, B. Payzin, F. Vural et al.
• Year: 2016
• Venue: Archives of Medical Science : AMS
• URL: https://www.semanticscholar.org/paper/fc49c78f799b61e1ca2683d050c925b9b52d5deb
• DOI: 10.5114/aoms.2015.53963
• PMID: 28261298
• PMCID: 5332439
• Citations: 7
• Influential citations: 1
• Summary: FAS/FASL gene expression may contribute to the molecular and immunological pathogenesis of CMPD, and more investigations are needed to support these data.
• Evidence snippets:
• Snippet 1 (score: 0.462) > Chronic myeloproliferative disorders (CMPD) are pluripotent hematopoietic stem cell diseases, characterized by proliferation of one or more Clinical research myeloid cell lines (erythroid, granulocytic, megakaryocytic) in the bone marrow, without exhibiting any differentiation and maturation defect [1]. Common properties of these diseases include uncontrolled proliferation of one or more of the myeloid cell lines, relatively normal maturation, hepatosplenomegaly, transformation to acute leukemia in different proportions and development of bone marrow fibrosis [2]. Development, progression and myeloproliferative mechanisms of the disease are not quite clear yet. Molecular mechanisms as well as aberrant expression of the genes that regulate apoptosis are thought to play a role here too, as in other hematologic malignancies [3]. Impairment of the apoptosis mechanisms and aberrant expression of pro-antiapoptotic proteins contribute to the excessive cell proliferation and development of fibrosis [4]. The relationship between the impairment of apoptosis and various hematological malignancies (chronic neutrophilic leukemia, myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML), etc.) has been revealed in the literature [5]. Apoptosis is known as programmed cell death [6,7]. It occurs through two main mechanisms: either a change in the mitochondrial permeability (intrinsic pathway) or binding of the death receptor and the specific ligand on the cell surface (extrinsic pathway) [8,9]. FAS (CD95) is a molecule expressed on the cell surface, and it initiates the death signal after binding to its ligand (FASL) [10]. The FAS/FASL pathway is a critical system for hematopoietic cell survival and apoptosis [11][12][13]. Genetic variations in the promoter region of FAS/FASL may play an important role in the pathogenesis of CMPD by inducing apoptosis.

[3] Molecular Pathogenesis in Myeloid Neoplasms with Germline Predisposition

• Authors: Juehua Gao, Yihua Chen, M. Sukhanova
• Year: 2021
• Venue: Life
• URL: https://www.semanticscholar.org/paper/e92b2ee66272a4073ff4b6dfa5993cb9e23c577c
• DOI: 10.3390/life12010046
• PMID: 35054439
• PMCID: 8779845
• Citations: 5
• Summary: This review uses examples of these disorders to illustrate the key molecular pathways of myeloid neoplasms and models and tools that can further understand the biology and molecular mechanisms of this disease.
• Evidence snippets:
• Snippet 1 (score: 0.456) > Myeloid neoplasms with germline predisposition have been increasingly recognized in clinical practice. Table 2 includes genes with a recognized inherited predisposition to myeloid neoplasms, but the rapidly expanding list of genes is well beyond the ones presented in this review. Although the incidence of myeloid neoplasms with germline predisposition is still poorly defined and the molecular pathogenesis has not entirely been elucidated for many of these entities, these cases provide unique and important insights into the biology and molecular mechanisms. An oversimplified molecular mechanism of myeloid neoplasms with germline predisposition is summarized in Figure 1. We continue to gain knowledge about the regulation of the germline genetic defects and their interactions with other genes and proteins, the role of the bone marrow microenvironment, the genotype/phenotype correlations, the clinical presentations, and the longitudinal dynamics during the process of disease progression. This group of inherited hematologic conditions offers a unique model for a better understanding of the mechanism of the development of myeloid neoplasms and disease progression. This knowledge will eventually translate into improved sub-classification, risk assessment, and development of effective therapies beyond standard options. SRP72 is a component of the signal recognition particle, a ribonucleoprotein complex responsible for the translocation of nascent membrane-bound and excreted proteins to the endoplasmic reticulum. > [68] > AML: acute myeloid leukemia, MDS: myelodysplastic syndrome; PV: polycythemia vera; ET: essential thrombocythemia; PMF: primary myelofibrosis; CMML: chronic myelomonocytic leukemia; CML: chronic myeloid leukemia; aCML: atypical chronic myeloid leukemia.

[4] Genetic disruption of the PI3K regulatory subunits, p85α, p55α, and p50α, normalizes mutant PTPN11-induced hypersensitivity to GM-CSF

• Authors: Charles B. Goodwin, Zhenyun Yang, F. Yin, Menggang Yu, R. Chan
• Year: 2012
• Venue: Haematologica
• URL: https://www.semanticscholar.org/paper/939f0cbac8d549d4863a0b73570dfb2917991eb0
• DOI: 10.3324/haematol.2011.046896
• PMID: 22315502
• Citations: 17
• Summary: It is shown that treatment with the p110δ-specific inhibitor, IC87114, or the clinical grade pan-phosphoinositide-3-kinase inhibitor, GDC-0941, reduced granulocyte macrophage-colony stimulating factor hypersensitivity.
• Evidence snippets:
• Snippet 1 (score: 0.449) > Juvenile myelomonocytic leukemia is a lethal disease of children characterized by hypersensitivity of hematopoietic progenitors to granulocyte macrophage-colony stimulating factor. Mutations in PTPN11, the gene encoding the protein tyrosine phosphatase Shp2, are common in juvenile myelomonocytic leukemia and induce hyperactivation of the phosphoinositide-3-kinase pathway. We found that genetic disruption of Pik3r1, the gene encoding the Class IA phosphoinositide-3-kinase regulatory subunits p85α, p55α and p50α, significantly reduced hyperproliferation and hyperphosphorylation of Akt in gain-of-function Shp2 E76K-expressing cells. Elevated protein levels of the phosphoinositide-3-kinase catalytic subunit, p110δ, in the Shp2 E76K-expressing Pik3r1−/− cells suggest that p110δ may be a crucial mediator of mutant Shp2-induced phosphoinositide-3-kinase hyperactivation. Consistently, treatment with the p110δ-specific inhibitor, IC87114, or the clinical grade pan-phosphoinositide-3-kinase inhibitor, GDC-0941, reduced granulocyte macrophage-colony stimulating factor hypersensitivity. Treatment with the farnesyltransferase inhibitor, tipifarnib, showed that Shp2 E76K induces hyperactivation of phosphoinositide-3-kinase by both Ras-dependent and Ras-independent mechanisms. Collectively, these findings implicate Class IA phosphoinositide-3-kinase as a relevant molecular target in juvenile myelomonocytic leukemia.

[5] Motivating medical students to learn basic science concepts using chronic myeloid leukemia as an integration theme

• Authors: S. Saad, H. F. Carvalho
• Year: 2014
• Venue: Revista Brasileira de Hematologia e Hemoterapia
• URL: https://www.semanticscholar.org/paper/c4b4a23d127d973f2c5d5193ee708ba5fd1bb4eb
• DOI: 10.1016/j.bjhh.2014.08.002
• PMID: 25638771
• PMCID: 4318846
• Citations: 1
• Summary: Chronic myeloid leukemia is an excellent example of a disease that can be used for clinical basic integration as this disorder involves well known protein, cytogenetic and cell function abnormalities, has well-defined diagnostic strategies and a target oriented therapy.
• Evidence snippets:
• Snippet 1 (score: 0.446) > The aim of 'The Cell' course is to provide a basis to understand the main aspects of normal and abnormal molecular and cellular functioning of different systems. > The clinical case, approached during the entire course, provides the student with the opportunity to acquire basic and up-to-date knowledge regarding cell structure and function. Using chronic myeloid leukemia as an integration theme, students learn about cell dynamics, including structural and biochemical aspects of cell components, such as proteins, carbohydrates and lipids, biomembranes and organelles, receptors and signal transduction, chromatin and chromosomes, gene regulation, proliferation mechanisms, migration, adhesion, differentiation and cell death among other issues. It was also important to prepare the student to understand the diagnostic and therapeutic techniques which have recently been developed or which are yet to be developed as well as to incorporate basic scientific knowledge in order to articulate diagnostic, therapeutic and prognostic practice. Moreover, the paper gives students the opportunity to analyze scientific information relevant to professional practice. > In conclusion, chronic myeloid leukemia is an excellent disease for clinical-basic integration as it comprises well known protein, cytogenetic and cell function abnormalities, has well defined diagnosis strategies and a target oriented therapeutics.

[6] Progression in Myeloid Neoplasms: Beyond the Myeloblast

• Authors: C. Faria, A. Tzankov
• Year: 2023
• Venue: Pathobiology
• URL: https://www.semanticscholar.org/paper/6482f862b71b1cec8db1453bbef5c44e331b0367
• DOI: 10.1159/000530940
• PMID: 37232015
• PMCID: 10857805
• Citations: 14
• Summary: MN with LB transformation is associated with secondary genetic events linked to lineage reprogramming leading to the deregulation of ETV6, IKZF1, PAX5, PU.1, and RUNX1, and the acquisition of MAPK-pathway gene mutations may shape MN toward histiocytic differentiation.
• Evidence snippets:
• Snippet 1 (score: 0.433) > Disease progression in myelodysplastic syndromes (MDS), myelodysplastic-myeloproliferative neoplasms (MDS/MPN), and myeloproliferative neoplasms (MPN), altogether referred to as myeloid neoplasms (MN), is a major source of mortality. Apart from transformation to acute myeloid leukemia, the clinical progression of MN is mostly due to the overgrowth of pre-existing hematopoiesis by the MN without an additional transforming event. Still, MN may evolve along other recurrent yet less well-known scenarios: (1) acquisition of MPN features in MDS or (2) MDS features in MPN, (3) progressive myelofibrosis (MF), (4) acquisition of chronic myelomonocytic leukemia (CMML)-like characteristics in MPN or MDS, (5) development of myeloid sarcoma (MS), (6) lymphoblastic (LB) transformation, (7) histiocytic/dendritic outgrowths. These MN-transformation types exhibit a propensity for extramedullary sites (e.g., skin, lymph nodes, liver), highlighting the importance of lesional biopsies in diagnosis. Gain of distinct mutations/mutational patterns seems to be causative or at least accompanying several of the above-mentioned scenarios. MDS developing MPN features often acquire MPN driver mutations (usually JAK2), and MF. Conversely, MPN gaining MDS features develop, e.g., ASXL1, IDH1/2, SF3B1, and/or SRSF2 mutations. Mutations of RAS-genes are often detected in CMML-like MPN progression. MS ex MN is characterized by complex karyotypes, FLT3 and/or NPM1 mutations, and often monoblastic phenotype. MN with LB transformation is associated with secondary genetic events linked to lineage reprogramming leading to the deregulation of ETV6, IKZF1, PAX5, PU.1, and RUNX1. Finally, the acquisition of MAPK-pathway gene mutations may shape MN toward

[7] Role of tyrosine-kinase inhibitors in myeloproliferative neoplasms: comparative lessons learned

• Authors: J. Pinilla-Ibarz, K. Sweet, Gabriela Corrales-Yepez, R. Komrokji
• Year: 2016
• Venue: OncoTargets and therapy
• URL: https://www.semanticscholar.org/paper/2a4d8192a5c552c921e5179fd8beb1411452c92e
• DOI: 10.2147/OTT.S102504
• PMID: 27570458
• PMCID: 4986686
• Citations: 15
• Summary: The role of tyrosine-kinase inhibitors in the current MPN-treatment landscape is discussed, underscoring the need for novel combination therapies of JAK inhibitors and complementary agents that better address the complexity of the pathobiology of classic Ph-negative MPNs.
• Evidence snippets:
• Snippet 1 (score: 0.430) > Myeloproliferative neoplasms (MPNs) are a heterogeneous group of hematologic malignancies characterized by the increased clonal proliferation of one or more myeloid lineages. 1,2 Classic MPNs include chronic myeloid leukemia (CML), primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET), whereas nonclassic MPNs include less common malignancies, such as chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia not otherwise specified (CEL-NOS), mast-cell disease (mastocytosis), and MPNs unclassifiable. 3 MPNs are further divided into two groups based on the presence or absence of the Philadelphia chromosome (Ph), formed by a translocation event and housing the constitutively activated fusion tyrosine kinase (TK) gene BCR-ABL. 2 BCR-ABL positivity is exclusively associated with CML, whereas Ph-negative MPNs are a heterogeneous group that includes all other MPNs. 2 The identification of the BCR-ABL fusion gene in the pathogenesis of CML and the subsequent development of TK inhibitors (TKIs) that target the BCR-ABL fusion protein were major breakthroughs in cancer therapy and recognized as one of the best examples of rationally developed targeted drugs in oncology. Since then, characterization of mutations in other MPNs has improved the understanding of the pathogenesis of these diseases; however, unlike CML, the disease may be driven by more than one mutation or mechanism. Consequently, clinical development of specific TKIs has focused on targeting the abnormal signaling (eg, JAK pathway) involved in the pathogenesis of Ph-negative MPNs. The objective of this review is to provide the basis to understand the role of TKIs in the treatment of MPNs and why the mechanisms and benefits of therapeutic action differ between Ph-negative and Ph-positive diseases.

[8] The prognostic and therapeutic potential of HO-1 in leukemia and MDS

• Authors: M. Sadeghi, M. Fathi, Jamshid Gholizadeh Navashenaq, Hamed Mohammadi, M. Yousefi et al.
• Year: 2023
• Venue: Cell Communication and Signaling : CCS
• URL: https://www.semanticscholar.org/paper/ee7efa18f004845d885fd0779627dfd2c5c6d0b4
• DOI: 10.1186/s12964-023-01074-8
• PMID: 36915102
• PMCID: 10009952
• Citations: 14
• Summary: It was concluded that HO-1 induces tumor progression and prevents apoptosis through various pathways and has great potential in determining the prognosis of leukemia and MDS patients.
• Evidence snippets:
• Snippet 1 (score: 0.429) > Page 2 of 21 Sadeghi et al. Cell Communication and Signaling (2023) 21:57 Background Myelodysplastic Syndromes (MDSs), a group of blood disorders with poorly defined pathophysiology, are known as conditions in which impaired maturation of blood cells in Bone Marrow (BM) is observed, resulting in different degrees of cytopenia in the Peripheral Blood (PB) [1]. Near one-third of MDS progress to Acute Myeloid Leukemia (AML), while the other two-thirds are transformed into high-risk MDS [2]. Leukemia is characterized by the excess of White Blood Cells (WBCs) in the PB and BM of patients [3][4][5]. Clinically, this disease can be divided into 4 major categories; based on the origin of the affected cells to lymphoid and myeloid and based on the percentage of blasts to chronic and acute leukemia. The major groups of leukemia comprise four common categories including Acute Lymphoblastic Leukemia (ALL), Chronic Lymphoblastic Leukemia (CLL), Chronic Myeloid Leukemia (CML), and AML. Treatment of leukemia depends on the type of disease, the patient's age, and general health. The firstline treatment for all types of leukemia is mainly chemotherapy, except for CML which involves Tyrosine Kinase Inhibitors (TKIs) [6]. However, radiation therapy, Hematopoietic Stem Cell Transplantation (HSCT), targeted therapy, as well as a combination of these approaches may also be utilized. Despite this, due to the high toxicity of the chemotherapeutics [7], and the possibility of rising chemo-resistant clones of malignant cells in many patients, there is a need for novel treatment approaches that efficiently kill chemo-resistant clones and reduce the required dose of the drugs [3,8,9]. Numerous factors can contribute to resistance to chemotherapy. A crucial factor is the increased or abnormal expression of Heme Oxygenase-1 (HO-1). HO-1 causes treatment resistance by several mechanisms including the induction of autophagy [10], cell survival, and by its anti-inflammation, and anti-oxidant properties [11]

[9] HOXA4 Gene Promoter Hypermethylation as an Epigenetic Mechanism Mediating Resistance to Imatinib Mesylate in Chronic Myeloid Leukemia Patients

• Authors: M. H. Elias, A. Baba, A. Husin, S. Sulong, R. Hassan et al.
• Year: 2012
• Venue: BioMed Research International
• URL: https://www.semanticscholar.org/paper/b2993bb3805474485fc051a260b75c2ca6fd8f88
• DOI: 10.1155/2013/129715
• PMID: 23484077
• PMCID: 3591123
• Citations: 34
• Influential citations: 2
• Summary: Investigation of the promoter hypermethylation status of HOXA4 in CML patients on IM treatment and its role in mediating resistance to IM found its role was reasonable and it was reasonable to suggest that promoterHypermethylation of HOxA4 gene could be an epigenetic mechanism mediating IM resistance in C ML patients.
• Evidence snippets:
• Snippet 1 (score: 0.427) > Chronic myeloid leukemia (CML) is a myeloproliferative disorder that comprises 14% of all leukemias. e molecular pathogenesis of CML involves the clonal expansion of pluripotent haematopoietic stem cells containing the BCR-ABL fusion oncogene. BCR-ABL gene results from a reciprocal translocation between chromosome 9 and 22 to form the Philadelphia chromosome [1]. is BCR-ABL fusion gene codes for a p210 kD protein with increased tyrosine kinase activity. Imatinib mesylate (IM) or Glivec (NOVARTIS Pharma) is a selective molecular inhibitor of the BCR-ABL oncogene protein and permits long term disease control in about two thirds of chronic phase CML patients [2]. IM has dramatically improved the treatment of CML and is generally considered as frontline therapy for CML patients. Despite its striking efficacy, development of resistance in signi�cant proportion of CML patients on IM therapy has emerged as a major clinical problem affecting both patients and treating physicians. > Various mechanisms of resistance and suboptimal response to IM have been described, involving BCR-ABL1-dependent and BCR-ABL1-independent pathways [3,4]. BCR-ABL1-dependent mechanism usually involves point mutations in the tyrosine kinase domain (TKD) and ampli�cation of BCR-ABL gene, with mutations in the BCR-ABL tyrosine kinase domain being better characterized [5]. Our previous study on BCR-ABL TKD mutation analysis showed that BCR-ABL mutations accounted for IM resistance in only 21.7% of Malaysian CML patients on IM therapy (communicated separately; in Press). is indicated that BCR-ABL mutations are not the only cause for relapse and resistance. It is presumed that the mechanisms of IM resistance in CML patients who do not have TKD mutation might be mediated through BCR-ABL-independent pathways. However, the exact mechanism in BCR-ABLindependent pathway still remains unclear, despite several genetic and epigenetic mechanisms postulated to be involved in the BCR-ABL-independent pathway.

[10] Novel drug therapies in myeloid leukemia.

• Authors: G. Horne, Ross Kinstrie, M. Copland
• Year: 2015
• Venue: Pharmaceutical patent analyst
• URL: https://www.semanticscholar.org/paper/73ebc2c2700940554131391da4921cd6c7025c23
• DOI: 10.4155/ppa.15.3
• PMID: 26030080
• Citations: 18
• Influential citations: 1
• Summary: This review focuses on clinically relevant patent applications and their relevance within the known literature in two areas of prevailing therapeutic interest, namely monoclonal antibody therapy and small molecule inhibitors in disease-relevant signaling pathways.
• Evidence snippets:
• Snippet 1 (score: 0.422) > Both acute myeloid leukemia and chronic myeloid leukemia are thought to arise from a subpopulation of primitive cells, termed leukemic stem cells that share properties with somatic stem cells. Leukemic stem cells are capable of continued self-renewal, and are resistant to conventional chemotherapy and are considered to be responsible for disease relapse. In recent years, improved understanding of the underlying mechanisms of myeloid leukemia biology has led to the development of novel and targeted therapies. This review focuses on clinically relevant patent applications and their relevance within the known literature in two areas of prevailing therapeutic interest, namely monoclonal antibody therapy and small molecule inhibitors in disease-relevant signaling pathways. > Myeloid leukemias are characterized by the accumulation of immature myeloid progenitors caused by aberrations in cellular function, where deregulation of differentiation, growth and apoptosis leads to progression of an oncogenic phenotype [1][2][3]. The two commonest types of myeloid leukemia represent distinct disease entities -acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). Improved understanding of the underlying mechanisms in their leukemic biology has led to the development of novel and targeted therapies. CML represents a prime example of the role that targeted therapies can play in improved disease outcome. CML is a clonal myeloproliferative disorder associated with a reciprocal translocation between the long arms of chromosomes 22 and 9 giving rise to the Philadelphia chromosome and the subsequent formation of the BCR-ABL fusion gene, encoding the constitutively active tyrosine kinase BCR-ABL [4][5][6][7]. Advances in targeted therapies in chronic phase CML, notably the use of tyrosine kinase inhibitors (TKIs), have led to a tenfold reduction in disease progression to an accelerated or blast phase [8]. However, if left untreated, or in patients where resistance to TKIs exists or develops, the dis-ease eventually progresses to blast phase, with terminal outcome in most cases [9,10].

[11] Recent insights regarding the molecular basis of myeloproliferative neoplasms

• Authors: Mi-Ae Jang, C. Choi
• Year: 2019
• Venue: The Korean Journal of Internal Medicine
• URL: https://www.semanticscholar.org/paper/8eb0d016e7cd618c5792e7e6b755267918420c9d
• DOI: 10.3904/kjim.2019.317
• PMID: 31778606
• PMCID: 6960053
• Citations: 38
• Influential citations: 1
• Summary: This review summarizes the current understanding of the genetic basis of MPNs, and demonstrates how molecular pathophysiology can improve both the understanding of MPN heterogeneity and clinical practice.
• Evidence snippets:
• Snippet 1 (score: 0.413) > Myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal disorders characterized by the overproduction of mature blood cells that have an increased risk of thrombosis and progression to acute myeloid leukemia. Next-generation sequencing studies have provided key insights regarding the molecular mechanisms of MPNs. MPN driver mutations in genes associated with the JAK-STAT pathway include JAK2 V617F, JAK2 exon 12 mutations and mutations in MPL, CALR, and CSF3R. Cooperating driver genes are also frequently detected and also mutated in other myeloid neoplasms; these driver genes are involved in epigenetic methylation, messenger RNA splicing, transcription regulation, and signal transduction. In addition, other genetic factors such as germline predisposition, order of mutation acquisition, and variant allele frequency also influence disease initiation and progression. This review summarizes the current understanding of the genetic basis of MPN, and demonstrates how molecular pathophysiology can improve both our understanding of MPN heterogeneity and clinical practice.

[12] Proliferative activity is disturbed in myeloproliferative neoplasms (MPN), myelodysplastic syndrome (MDS), and MDS/MPN diseases. Differences between MDS and MDS/MPN

• Authors: Stefan G. C. Mestrum, Norbert C. J. de Wit, R. Drent, A. Hopman, F. Ramaekers et al.
• Year: 2020
• Venue: Cytometry. Part B, Clinical Cytometry
• URL: https://www.semanticscholar.org/paper/1e241ecd7216cf036651543ff9039b8a09a3efee
• DOI: 10.1002/cyto.b.21946
• PMID: 32857909
• PMCID: 8247351
• Citations: 17
• Summary: To what extent the proliferative activity, as determined by Ki‐67 expression, is disturbed in myeloproliferative neoplasms (MPN), myelodysplastic syndrome (MDS), and MDS/MPN diseases is investigated to gain a better understanding into the pathobiology of these malignancies.
• Evidence snippets:
• Snippet 1 (score: 0.412) > This clonal myeloid disorder, with clinical, molecular, and morphological features that overlap between MDS and MPN, consists of four major myeloid disorders. These disorders include chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia, atypical CML and, since the last revision of the WHO classification, also MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T). > Their shared features include cellular dysplasia and/or cytopenias, characteristics of MDS, in addition to cytosis, a characteristic of MPN. > At the molecular level, MDS/MPN are more likely to carry gene mutations associated with the activation of growth factor signaling pathways, a characteristic of MPN. > Ki-67 is a nuclear proliferation marker, expressed during the late G1-, S-, G2-, and M-phases of the cell cycle (Gerdes et al., 1984). > Expression of Ki-67 is associated with the organization of chromosomes and is therefore strongly associated with cell proliferation (Cuylen et al., 2016;Verheijen et al., 1989). Knock-out of Ki-67 results in cell-cycle arrest, which further supports the role of Ki-67 in the progression of the cell cycle. In diagnostic histopathology, Ki-67 is widely and routinely used as an immunohistochemical marker for proliferative activity in various types of solid tumors and has been shown to correlate with the clinical outcome of a broad spectrum of malignant diseases, including non-Hodgkin lymphoma (Demurtas et al., 2013;Trihia et al., 2003;Wei et al., 2018). > In the diagnostic work-up of myeloid disorders, immunocytochemical analysis is mostly performed by flow cytometry in which, surprisingly, the Ki-67 marker is only rarely used.

[13] Cytotoxic Marine Alkaloid 3,10-Dibromofascaplysin Induces Apoptosis and Synergizes with Cytarabine Resulting in Leukemia Cell Death

• Authors: P. Spirin, E. Shyrokova, T. Lebedev, E. Vagapova, Polina A. Smirnova et al.
• Year: 2021
• Venue: Marine Drugs
• URL: https://www.semanticscholar.org/paper/86900fe3aeb46765e851267c4639ea7eb511352a
• DOI: 10.3390/md19090489
• PMID: 34564151
• PMCID: 8468638
• Citations: 13
• Summary: DBF is a promising drug candidate, which may be used in combinational therapeutics approaches to reduce leukemia cell growth, and synergistically increase the cytotoxic effect of cytarabine in different myeloid leukemia cell lines.
• Evidence snippets:
• Snippet 1 (score: 0.409) > Myeloid leukemia is a group of heterogeneous malignant disorders characterized by uncontrolled clonal proliferation of primitive hematopoietic stem or progenitor cells.This disease is divided into two subgroups according to the type of affected blood cell and its chronic or acute forms and include acute myeloid leukemia (AML) and chronic myeloid leukemia (CML).The mechanisms underlying development of myeloid leukemia are still not clearly understood.However, mutations in genes whose proteins are involved in the development of blood precursor cells seems to play a crucial role by causing rearmaments of signaling pathways disturbing the normal hematopoiesis [1][2][3][4].The chemotherapy with cytarabine (AraC) and anthrayclines is widely used to treat AML [5].Targeted treatment approaches represent a promising strategy [6].For example, the introduction to the CML therapy of BCR/ABL inhibitor imatinib raised up to 90% the overall 5-year survival of CML patients.To date, disease persistence and recurrence remain a major challenge in myeloid leukemia therapy [5,7,8].Potential targets for treating myeloid leukemias comprise receptors of tyrosine kinases [9][10][11][12], proteins contributing to the drug resistance and mutated proteins [13,14], kinases involved in pro-survival signaling pathways [11,13,15,16], components of DNA-reparation system [17,18] as well as kinases involved in cell cycle regulation and autophagy [19][20][21].Remarkably, CDK4 and CDK6 kinases are frequently overexpressed in leukemia and responsible for G1 to S phase cell cycle transition via retinoblastoma protein (RB) dependent activation of an E2F1 transcription factor.An inhibitor of CDK4/6, palbociclib (PD-0332991), was previously approved by FDA for treatmet of breast cancer and is currently undergoing several clinical trials in other malignancies [22][23][24].

[14] The EHA Research Roadmap: Malignant Myeloid Diseases

• Authors: H. Döhner, L. Malcovati, G. Ossenkoppele, A. Hochhaus, Alessandro Maria Vannucchi et al.
• Year: 2021
• Venue: HemaSphere
• URL: https://www.semanticscholar.org/paper/5537a661976d45f5225d4f60659be264a7c50e32
• DOI: 10.1097/HS9.0000000000000635
• PMID: 34476345
• PMCID: 8389885
• Citations: 3
• Summary: he malignant myeloid diseases discussed in this section are clonal disorders of hematopoietic stem cells (HSCs) and progenitor cells with various underlying molecular basis, different clinical phenotypes and largely differing prognosis. Although younger patients may be affected
• Evidence snippets:
• Snippet 1 (score: 0.409) > In the past few years, major advances in the understanding of the genetic basis of MDS have been made by means of massive parallel DNA sequencing, and a number of seminal studies have been performed in Europe. [2][3][4][5][6] Approximately, 90% of MDS patients carry one or more oncogenic mutations with two-thirds of them are found in individuals with a normal karyotype. Driver mutations have been identified in genes involved in RNA splicing, DNA methylation, chromatin modification, transcription regulation, DNA repair, and signal transduction. Only a few genes are consistently mutated in 10% or more MDS patients, including those involved in epigenetic regulation (TET2, ASXL1, and DNMT3A) and splicing factors (SF3B1, SRSF2, and U2AF1), while a long tail of >50 genes are mutated less frequently. 3,4 Mutations in SF3B1 have been found to be highly specific for MDS with ring sideroblasts and are associated with a very low risk of disease progression and a favorable outcome. 5 European hematologists have provided pivotal contributions to developing effective treatments for MDS, including erythropoietin, azacitidine, lenalidomide, and luspatercept. [7][8][9] Recommendations for treatment of the individual patient with MDS, including allogeneic HSCT, have also been developed in recent years. [10][11][12] Seminal contributions have also been made in pediatric hematology, for example, in elucidating the genetic predisposition to juvenile myelomonocytic leukemia, as well as to MDS or other myeloid neoplasms. 13 Proposed research for the Roadmap Myeloid malignancies appear to be propagated by rare self-renewing mutant HSCs. However, the cellular and molecular mechanisms that regulate development, propagation, and therapy resistance of these myelodysplastic stem cells remain unknown. Studies are needed to: > 1. characterize cellular and molecular mechanisms involved in disease development, progression and therapy resistance, including germline predisposition, chronic inflammation, microenvironmental and im

[15] Infection and Potential Challenge of Childhood Mortality in Sickle Cell Disease: A Comprehensive Review of the Literature from a Global Perspective

• Authors: Tarun Sahu, Babita Pande, H. Verma, L. Bhaskar, Meenakshi Sinha et al.
• Year: 2023
• Venue: Thalassemia Reports
• URL: https://www.semanticscholar.org/paper/e7ada26efa25d2b0e4332b651bf95e0dabfd1d66
• DOI: 10.3390/thalassrep13030019
• Citations: 12
• Influential citations: 1
• Summary: The need for targeted interventions, improved healthcare access, vaccination programs, and infection prevention strategies to alleviate the impact of infections on individuals with SCD and reduce the global mortality rates associated with the disease is emphasized.
• Evidence snippets:
• Snippet 1 (score: 0.407) > SCD patients are susceptible to infections due to a variety of immunological abnormalities and exposure to infectious agents. Pathophysiological mechanisms of the disease can explain the disease's role in stimulating immune dysfunction. The clinical manifestations of infection in SCD are primarily vaso-occlusion, which causes endothelial dysfunction and hemolysis. The detailed molecular mechanism involved in the clinical manifestations of SCD is depicted in Figure 1. > of developing an associated bone-joint infection if they are not adequately treated [42] 3.8. Molecular Mechanism of Clinical Manifestations in SCD SCD patients are susceptible to infections due to a variety of immunologi abnormalities and exposure to infectious agents. Pathophysiological mechanisms of disease can explain the disease's role in stimulating immune dysfunction. The clini manifestations of infection in SCD are primarily vaso-occlusion, which causes endothe dysfunction and hemolysis. The detailed molecular mechanism involved in the clini manifestations of SCD is depicted in Figure 1. Hematocrit, plasma viscosity, and erythrocyte deformability are some factors th affect blood rheology. Sickled RBCs become mechanically trapped in the microcirculati promoting adhesive events among blood cells and resulting in chronic vaso-occlusi causing frequent episodes of pain, hemolytic anemia, organ damage, and premature dea [43,44]. Sickled RBCs also promote the exposure of adhesion molecules and binding mo that are not generally found on RBCs' outer membranes, such as phosphatidyl serine (P basal cell adhesion molecule-1 (B-CAM1), integrin-associated protein (IAP), a intercellular-adhesion-molecule-4 (ICAM-4). Sickled RBCs also have an integrin comp on their surface, which binds to fibronectin and vascular-cell adhesion molecule (VCAM1), expressed on endothelial cells' membrane and activated by inflammato cytokines like tumor necrosis factor-alpha.

[16] DyNDG: Identifying Leukemia-related Genes Based on Time-series Dynamic Network by Integrating Differential Genes

• Authors: Jin A, Ju Xiang, Xiangmao Meng, Yue Sheng, Hongling Peng et al.
• Year: 2025
• Venue: Genomics, Proteomics & Bioinformatics
• URL: https://www.semanticscholar.org/paper/d59ea884b9c1a8f73feb59e600b3df771c646118
• DOI: 10.1093/gpbjnl/qzaf037
• PMID: 40300112
• PMCID: 12417087
• Citations: 2
• Influential citations: 1
• Summary: A novel Dynamic Network-based model integrating Differentially expressed Genes (DyNDG) to identify leukemia-related genes yields a set of promising candidate genes associated with leukemia progression or potential biomarkers, indicating the value of dynamic network information in identifying leukemia-related genes.
• Evidence snippets:
• Snippet 1 (score: 0.402) > CML is a chronic leukemia caused by the fusion of the BCR and ABL genes. Inhibiting the activity of the BCR-ABL fusion protein with tyrosine kinase inhibitors (TKIs) can effectively control the proliferation and survival of CML cells, leading to sustained clinical and molecular remission in the majority of patients. However, long-term use of TKIs may result in side effects, and some patients may develop resistance or intolerance to TKI treatment [66]. By applying DyNDG to CML, predicting genes associated with its disease progression may provide valuable insights for studying new targets in CML, addressing the issue of drug resistance, and exploring novel therapeutic approaches for CML. Functional enrichment analysis conducted on the top 1% candidate genes revealed the KEGG pathways and GO terms most related to CML, as shown in Figure 7A and B, respectively. The bar chart illustrates the outcomes of GO enrichment analysis, highlighting the most relevant GO terms associated with CLL. C. The Sankey diagrams show the associations between GO terms and multi-pathway enriched genes, as well as the associations between KEGG pathways and multi-pathway enriched genes. D. The network graph reflects the degree centrality of candidate genes enriched in CLL-related pathways and known CLL-related genes. > The KEGG pathways most relevant to CML include cancer-related pathways (such as cell cycle, PI3K-Akt signaling pathway, and proteoglycans in cancer), the pathways closely associated with the immunity (such as Th1 and Th2 cell differentiation), and pathways associated with chronic leukemias (such as chronic myeloid leukemia and leukocyte transendothelial migration). GO enrichment analysis revealed numerous CML-related biological processes (such as leukocyte cell-cell adhesion, leukocyte proliferation, myeloid leukocyte differentiation, and leukocyte mediated immunity), molecular functions (such as DNA-binding transcription factor binding and ubiquitin-like protein ligase binding), and cellular components (such as chromosomal regions).

[17] CX‑5461 potentiates imatinib‑induced apoptosis in K562 cells by stimulating KIF1B expression

• Authors: Chaochao Dai, Xiaopei Cui, Jie Wang, Bo Dong, Haiqing Gao et al.
• Year: 2024
• Venue: Experimental and Therapeutic Medicine
• URL: https://www.semanticscholar.org/paper/2e21b36bd3391cd3cb71e37a63f1ae5783d0cd43
• DOI: 10.3892/etm.2024.12395
• PMID: 38356673
• PMCID: 10865453
• Citations: 1
• Summary: The results suggested that the synergistic interaction between CX-5461 and imatinib may be of potential clinical value for the treatment of tyrosine kinase inhibitor-resistant chronic myeloid leukemia.
• Evidence snippets:
• Snippet 1 (score: 0.401) > Chronic myeloid leukemia (CML) and Philadelphia Chromosome (Ph)-positive acute lymphoblastic leukemia are caused by expression of the oncogenic fusion protein Bcr-Abl, which is a constitutively active tyrosine kinase (1). Malignant transformation of affected cells by Bcr-Abl is mediated by a number of signaling mechanisms, including pathways of PI3K/Akt, mitogen-activated protein kinases, RhoA-Rac, and JAK/STAT, leading to dysregulation of cell survival, proliferation, differentiation and metabolism (2,3). Tyrosine kinase inhibitors (TKIs) such as imatinib and dasatinib, which target the binding of Bcr-Abl with ATP, have been successfully used in the treatment of CML. However, a major challenge associated with the use of these drugs in the clinic is the development of resistance (4). It has been shown that primary or acquired resistance occurs in >20% of CML patients undergoing imatinib treatment (5). > TKI resistance can be mediated by Bcr-Abl-dependent and -independent mechanisms. Bcr-Abl-dependent resistance is primarily caused by mutations (e.g. the well characterized T315I mutation) in the kinase domain of Abl (4). By comparison, the mechanisms of Bcr-Abl-independent resistance remain to be elucidated. It has been recognized that compensatory activation of the Akt/mTOR pathway and/or inactivation of the p53 gene are involved in this process (6,7). In fact, Bcr-Abl-independent resistance has particular clinical significance, because in the presence of effective kinase inhibition, Bcr-Abl-independent resistance may be a major contributor to the maintenance of minimal residual disease and relapse of CML (4). Supporting this notion, evidence shows that reactivation of the p53 pathway, either directly or indirectly, may boost the eradication of CML leukemia stem cells, which are thought to be TKI resistant (8)(9)(10).

[18] Study of intracellular signaling pathways in Chronic Myeloproliferative Neoplasms

• Authors: S. Martinelli
• Year: 2018
• Venue: Unknown venue
• URL: https://www.semanticscholar.org/paper/224169bcbcb34b521a355513157d139a9eb3df61
• DOI: 10.36253/978-88-6453-565-4
• Summary: The findings of strong synergy between the JAK2 inhibitors and mTOR/PI3K inhibitor suggested that the authors might be able to administer these drugs at lower concentrations than when the drugs are used individually.
• Evidence snippets:
• Snippet 1 (score: 0.400) > number of studies showed that the Myeloproliferative Diseases and other related blood disorders derived from the proliferation of the pluripotent stem cell and that clinical and phenotypic diversity is linked to different mutations in genes coding for proteins with tyrosine-kinase function (Kozbor D et al, 1986). In this regard the discovery of the Philadelphia crPh translocation and BCR-ABL1 as molecular marker of Chronic Myeloid Leukemia has certainly represented a turning point (Bartram CR et al., 1983). > In 2001 the World Health Organization formed the Myeloproliferative Diseases part of Chronic Myeloproliferative Diseases with also Chronic Neutrophilic Leukemia, Chronic Eosinophilic Leukemia / Hypereosinophilic Syndrome and Chronic Myeloproliferative Diseases unclassifiable (Jaffe ES et al., 2001). The criteria proposed by the WHO was based on the integration of clinical, laboratory and histopathological data for diagnosis and for the first time was given relief to the bone marrow biopsy as necessary for a correct diagnosis of ET and PMF and a complementary tool in the diagnosis of PV. However, the differential diagnosis between MPN Ph-negative was often difficult due to the lack of specific cytogenetic abnormalities and the frequent overlap of the clinical features between the different entities with both myelodysplastic syndromes / myeloproliferative diseases (eg. The atypical chronic myeloid leukemia and leukemia chronic myelomonocytic) and so-called reactive forms. The WHO criteria in 2001 were valid until have been described genetic mutations which were able to induce phenotypes similar to those of MPN in experimental animal models (Levine RL et al., 2005;James C et al., 2005). These recurrent anomalies strengthened the original vision of Dameshek, according to which these hematologic disorders are supported by a common pathogenic mechanism (Dameshek W, 1951). > In the light of this recent findings, in 2008 the WHO has revised the classification of hematological pathologies (Swerdlow SH et al., 2008) (Table 1). The Chronic Myeloproliferative Deseases were renamed in Myeloproliferative Neoplasms because of the clonal

[19] Inhibition of BCR::ABL1 tyrosine kinase activity Aids in the Generation of Stable Chronic Myeloid Leukemia Induced Pluripotent Stem Cells

• Authors: E. Benjamin, D. Babu, Gaurav Joshi, B. Rajamani, K. Nandy et al.
• Year: 2026
• Venue: bioRxiv
• URL: https://www.semanticscholar.org/paper/9f1c7ea64103a3d56b37ad961ba641da2f350520
• DOI: 10.1101/2023.06.01.543015
• Summary: This robust protocol for generating CML-iPSCs from CD34+ hematopoietic progenitors of CML patients with varying responses to tyrosine kinase inhibitor (TKI) therapy indicates that suppressing the BCR::ABL1 oncogenic pathway is essential for efficiently generating stable CML -iPSC colonies.
• Evidence snippets:
• Snippet 1 (score: 0.400) > Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that arises from hematopoietic stem cells (HSCs) transformed by BCR::ABL1 oncogenic fusion protein with constitutive serine/threonine kinase activity expressed in these cells. BCR::ABL1 triggers various downstream signaling pathways, including RAS/RAF/MEK/ERK, JAK2/STAT, and PI3K/AKT/mTOR pathways, leading to the accumulation of granulocytes at various stages of myeloid maturation (1,2). Although targeted therapy with tyrosine kinase inhibitors (TKIs), such as imatinib (IM), dasatinib (DA), and nilotinib (NIL), has dramatically improved the long-term survival of CML patients, only around 50% of patients achieve treatment-free remission (TFR) (3). The persistence of leukemic stem cells (LSCs) is one of the primary causes of disease recurrence (4). Due to the rarity of the LSC population, it is challenging to obtain sufficient cells for research to understand the mechanisms of TKI resistance of these cells and screen drugs to eradicate them (4,5). > Induced pluripotent stem cells (iPSCs) derived from patients with genetic diseases or cells with genetic alterations can be differentiated into scalable quantities of disease-relevant differentiated cells. Thus, they are a powerful tool for studying disease pathogenesis and drug screening (5). iPSCs generated from patients with leukemias help understand how oncogenes and patient-specific chromosomal abnormalities influence the development of leukemia-like phenotypes in-vitro (6). > CML-iPSCs generated from the same patient at various stages of the disease and from patients with different responses to TKI therapy are valuable resources for investigating molecular and epigenetic mechanisms of CML progression and drug resistance, leading to the identification of novel therapeutic targets and drug candidates for the treatment of CML (7,8). Moreover, iPSCs can be efficiently genetically manipulated by gene editing methods to identify specific genes involved in disease pathogenesis (9).

[20] Mechanisms underlying therapeutic resistance of tyrosine kinase inhibitors in chronic myeloid leukemia

• Authors: Jingnan Sun, R. Hu, Mengyuan Han, Yehui Tan, Mengqing Xie et al.
• Year: 2024
• Venue: International Journal of Biological Sciences
• URL: https://www.semanticscholar.org/paper/a2f6ebc57185793b1bca98cc63d97091d279b708
• DOI: 10.7150/ijbs.86305
• PMID: 38164178
• PMCID: 10750272
• Citations: 31
• Influential citations: 1
• Summary: The concept of resistance is discussed and recent advances exploring the mechanisms underlying CML resistance are summarized, which appears to be the most successful approach to reduce the burden of leukemia and enhance cures for CML.
• Evidence snippets:
• Snippet 1 (score: 0.397) > TKI resistance can be driven by ABL-dependent and independent mechanisms, depending on whether they are associated with the ABL kinase domain. Both mechanisms can induce significant clinical resistance, but secondary resistance usually involves ABLdependent pathways, such as BCR-ABL mutations, gene amplification, or increased expression [15,16]. ABL-independent resistance is more commonly seen in primary resistance, such as genomically unstable, quiescence leukemia stem cells, or individual differences in IM blood concentrations due to differences in oral bioavailability, the high affinity of serum proteins for IM, and cellular influx/efflux transporters [14,17,18] (Figure 1). > CML-chronic phase (CMP-CP) progression to CML-blastic phase (CML-BP) is a multifactorial, multi-step process. It is believed that disease progression may be triggered by a series of different but equivalent events [14]. ABL-dependent pathways and non-dependent pathways may work in synergy, leading to the accumulation of key events at the DNA, RNA, and protein levels, causing abnormal cell cycle control, differentiation, apoptosis failure, and eventually drug resistance.

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