Open AccessProsurvival kinase PIM2 is a therapeutic target for eradication of chronic myeloid leukemia stem cells
Author(s) -
Leyuan Ma,
Magnolia L. Pak,
Jianhong Ou,
Jun Yu,
Pamela St. Louis,
Yi Shan,
Lloyd Hutchinson,
Shaoguang Li,
Michael A. Brehm,
Lihua Julie Zhu,
Michael R. Green
Publication year - 2019
Publication title -
proceedings of the national academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.1903550116
Subject(s) - biology , myeloid leukemia , stem cell , cancer research , haematopoiesis , imatinib mesylate , abl , k562 cells , breakpoint cluster region , kinase , leukemia , gene , imatinib , microbiology and biotechnology , signal transduction , immunology , tyrosine kinase , genetics
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.
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