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 hBim^i2+/+, hBim^i2+/-, and hBim^i2-/- mice after BCR-ABL1 induction, with more aggressive disease observed in hBim^i2-/- compared to hBim^i2+/+ mice. Strikingly, when transplanted into irradiated recipients, Bim deletion-harboring BM cells greatly accelerated CML onset. The hBim^i2-/- LSCs are less apoptotic and more competitive in reconstituting capacity compared to hBim^i2+/+ LSCs. In addition, the hBim^i2-/- LSCs were significantly less apoptotic compared to hBim^i2+/+ 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.

THESIS ADVISOR:
A/Prof. Ong Sin Tiong

ZOOM ID:
892 8538 3148

ZOOM PW:
089913