THE BIM DELETION POLYMORPHISM ENHANCES THE FITNESS OF CHRONIC MYELOID LEUKAEMIA STEM CELLS

Abstract

An intronic deletion polymorphism in BIM gene, resulting in impaired production of pro-apoptotic BIM isoforms, is associated with resistance to tyrosine kinase inhibitors (TKI) and higher relapse rates upon TKI cessation in patients with chronic myeloid leukaemia (CML), suggesting the BIM deletion could protect leukaemic stem cells (LSC) from TKIs. To study the role of the BIM deletion in the rare stem cell population, we created a mouse model phenocopying the effects of the human BIM deletion. We found that the Bim deletion has little effect on normal haematopoiesis. To study the effects on CML LSCs, we crossed the humanized Bim mouse into the ScltTA; BCR-ABL1 CML mouse. CML faithfully developed in hBimi2+/+, hBimi2+/-, and hBimi2-/- mice after BCR-ABL1 induction, with more aggressive disease observed in hBimi2-/- compared to hBimi2+/+ mice. Strikingly, when transplanted into irradiated recipients, Bim deletion-harboring BM cells greatly accelerated CML onset. The hBimi2-/- LSCs are less apoptotic and more competitive in reconstituting capacity compared to hBimi2+/+ LSCs. In addition, the hBimi2-/- LSCs were significantly less apoptotic compared to hBimi2+/+ cells with TKI treatment. Together, our data demonstrates that the effects of the Bim deletion reach into the LSC compartment of CML, and may serve as a useful model to identify novel strategies to enhance LSC eradication and cures in CML.