This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "resisting_cell_death#BCL-2 Family Rheostat Shift Toward Survival"). The module defines the expected pathophysiology structure; conforming nodes in disorder files should include the corresponding biological processes and causal edges, specialized to their tumor context. Key tumor-specific substitutions: follicular lymphoma uses t(14;18)-driven BCL2 overexpression; CLL/AML use BCL-2 or MCL-1 dependence (BH3-mimetic targets); many cancers evade apoptosis through TP53 loss disabling the PUMA/NOXA arm. Key conformance / treatment target: "resisting_cell_death#BCL-2 Family Rheostat Shift Toward Survival".
Apoptosis-Evasion Lesion
trigger
A lesion that biases the cell against apoptosis. Routes include overexpression of pro-survival BCL-2 family members (BCL-2, BCL-XL, MCL-1) via translocation or amplification, loss-of-function of the pro-apoptotic effectors BAX/BAK, silencing of BH3-only sensitizers, or loss of upstream p53 that transactivates PUMA and NOXA. Each lesion raises the apoptotic threshold so that pro-death signals from oncogenic stress fail to trigger cell death.
Downstream
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BCL-2 Family Rheostat Shift Toward Survival
Show evidence (1 reference)
"BCL-2 family proteins, which have either pro- or anti-apoptotic activities, have been studied intensively for the past decade owing to their importance in the regulation of apoptosis, tumorigenesis and cellular responses to anti-cancer therapy."
Establishes the BCL-2 family as the regulatory hub of apoptosis whose dysregulation drives tumorigenesis, supporting the apoptosis-evasion lesion as the trigger of this module. Evidence source is OTHER because this is a review article.
BCL-2 Family Rheostat Shift Toward Survival
central effector
The balance of the BCL-2 family is shifted so that pro-survival members sequester pro-apoptotic effectors and BH3-only proteins, preventing BAX/BAK oligomerization in the mitochondrial outer membrane. With mitochondrial outer-membrane permeabilization blocked, cytochrome c is not released and the apoptosome cannot form. This shifted rheostat is the conserved central node and the molecular target of BH3-mimetic drugs.
Downstream
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Impaired Apoptotic Execution and Cell Survival
Show evidence (1 reference)
"They control the point of no return for clonogenic cell survival and thereby affect tumorigenesis"
Describes BCL-2 family control over the commitment point for cell survival, the conserved central effector of apoptosis evasion modeled here. Evidence source is OTHER because this is a review article.
Impaired Apoptotic Execution and Cell Survival
consequence
With the intrinsic pathway blocked upstream, effector caspase activation fails and apoptotic execution is impaired. Cells carrying oncogenic and genotoxic stress that should have been culled instead survive and persist, providing a substrate for further malignant evolution and contributing to resistance to chemotherapy and radiotherapy, which act in part by triggering apoptosis.
Show evidence (1 reference)
"They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis."
Hanahan & Weinberg list resisting cell death as a core hallmark capability, the consequence modeled here. Evidence source is OTHER because this is a review article.