The BIM deletion polymorphism potentiates the survival of leukemia stem and progenitor cells and impairs response to targeted therapies.
Document Type
Article
Publication Date
1-1-2025
Original Citation
Yu M,
Nah G,
Krishnan V,
Sulaimi F,
Ng K,
Wang C,
Bhatt S,
Chuah C,
Bergstrom DE,
Ong S.
The BIM deletion polymorphism potentiates the survival of leukemia stem and progenitor cells and impairs response to targeted therapies. Leukemia. 2025;39(1):134-43.
Keywords
JMG, Animals, Bcl-2-Like Protein 11, Mice, Neoplastic Stem Cells, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Polymorphism, Genetic, Drug Resistance, Neoplasm, Imatinib Mesylate, Apoptosis, Cell Survival, Protein Kinase Inhibitors, Molecular Targeted Therapy
JAX Source
Leukemia. 2025;39(1):134-43.
ISSN
1476-5551
PMID
39438588
DOI
https://doi.org/10.1038/s41375-024-02418-0
Abstract
One sixth of human cancers harbor pathogenic germline variants, but few studies have established their functional contribution to cancer outcomes. Here, we developed a humanized mouse model harboring a common East Asian polymorphism, the BIM deletion polymorphism (BDP), which confers resistance to oncogenic kinase inhibitors through generation of non-apoptotic splice isoforms. However, despite its clear role in mediating bulk resistance in patients, the BDP's role in cancer stem and progenitor cells, which initiate disease and possess altered BCL-2 rheostats compared to differentiated tumor cells, remains unknown. To study the role of the BDP in leukemia initiation, we crossed the BDP mouse into a chronic myeloid leukemia (CML) model. We found that the BDP greatly enhanced the fitness of CML cells with a three-fold greater competitive advantage, leading to more aggressive disease. The BDP conferred almost complete resistance to cell death induced by imatinib in CML stem and progenitor cells (LSPCs). Using BH3 profiling, we identified a novel therapeutic vulnerability of BDP LSPCs to MCL-1 antagonists, which we confirmed in primary human LSPCs, and in vivo. Our findings demonstrate the impact of human polymorphisms on the survival of LSPCs and highlight their potential as companion diagnostics for tailored therapies.