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Significance Chronic myeloid leukemia (CML) is a hematopoietic cancer caused by the oncogenic fusion protein BCR-ABL. The first-line treatment for CML is the BCR-ABL inhibitor imatinib mesylate (IM). Like several other cancers, CML is propagated by a small population of stem cells, whose eradication is required to cure the disease. Unfortunately, CML stem cells (CMLSCs) are resistant to IM treatment. Here we show that PIM2, a serine/threonine kinase, is required for IM resistance in CMLSCs. Combined treatment with IM and a PIM inhibitor synergistically kills CMLSCs in culture and significantly prolongs survival in a mouse CML model, with a negligible effect on normal hematopoietic stem cells. Our results reveal a mechanism of IM resistance in CMLSCs that can be therapeutically targeted.

Prosurvival kinase PIM2 is a therapeutic target for eradication of chronic myeloid leukemia stem cells