Chromosome 5q deletion drives evolution of aneuploidy in myeloid neoplasms with complex karyotype - PubMed
3 hours ago
- #aneuploidy
- #AML
- #chromosome 5q deletion
- The deletion of chromosome 5q (del5q), in combination with TP53 mutations, drives the evolution of complex aneuploidy in hematopoietic stem and progenitor cells (HSPCs) in high-risk acute myeloid leukemias with complex karyotype (AML-CK).
- A patient-derived iPSC model showed that TP53-mutant HSPCs with del5q, but not TP53 mutation alone, evolve into highly aneuploid states following transient mitotic inhibition, mimicking the stepwise chromosomal changes seen in AML-CK patients.
- Aneuploid HSPCs and primary AML-CK samples share a conserved gene expression signature involving upregulation of PTEN, cohesins, and the anti-apoptotic factor BCL2, suggesting a common aneuploid cell state.
- The BCL2 inhibitor venetoclax effectively targeted BCL2-dependent aneuploid clones, with resistant clones switching lineage and upregulating alternative BCL2 family factors, revealing a therapeutic vulnerability in AML-CK.