Hsp70-Bim interaction mediated mitophagy as a potential therapeutic target for CML stem cells.

In chronic myeloid leukemia (CML), disease persistence in patients is maintained by leukemic stem cells (LSCs), which drive tyrosine kinase inhibitor (TKI) resistance. Autophagy has been proposed as a potential therapy to eradicate CML LSCs. Here, using a small-molecule inhibitor of Hsp70 (heat shock protein 70)-Bim (Bcl-2-interacting mediator of cell death) interaction, S1-10, we demonstrate that Hsp70-Bim is a target for CML stemness maintenance. Hsp70-Bim is driven by Bcr-Abl and mediates particularly stronger mitophagy in CML LSCs than differentiated CML cells and HSCs. The more selective mitophagy regulation of Hsp70-Bim than ULK1 (unc-51-like autophagy activating kinase 1) is illustrated. Pharmacological inhibition of Hsp70-Bim blocks mitophagy, leading to the differentiation of CML LSCs, loss of quiescence, and loss of LSC self-renewal potential. In the patient-derived xenograft (PDX) CML models, S1g-10 reduces the number of LSCs by more than 80% after two weeks of injection, without obvious toxicity on normal red blood cells.