期刊
LEUKEMIA
卷 29, 期 8, 页码 1668-1675出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2015.53
关键词
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资金
- National Institutes of Health [HL082978-01, CA04963920A2, 1R01CA178397, CA129528]
- Leukemia and Lymphoma Society [7036-01]
- clinical research scholarship of the Leukemia and Lymphoma Society
- Howard Hughes Medical Institute through the Med into Grad Initiative
- Graduate Research Fellowship from the University of Utah
- DNA/Peptide Core and Flow Cytometry Core (NCI Cancer Center) [P30 CA042014]
Targeted therapy of chronic myeloid leukemia (CML) is currently based on small-molecule inhibitors that directly bind the tyrosine kinase domain of BCR-ABL1. This strategy has generally been successful, but is subject to drug resistance because of point mutations in the kinase domain. Kinase activity requires transactivation of BCR-ABL1 following an oligomerization event, which is mediated by the coiled-coil (CC) domain at the N terminus of the protein. Here, we describe a rationally engineered mutant version of the CC domain, called CCmut3, which interferes with BCR-ABL1 oligomerization and promotes apoptosis in BCR-ABL1-expressing cells, regardless of kinase domain mutation status. CCmut3 exhibits strong proapoptotic and antiproliferative activity in cell lines expressing native BCR-ABL1, single kinase domain mutant BCR-ABL1 (E255V and T315I) or compound-mutant BCR-ABL1 (E255V/T315I). Moreover, CCmut3 inhibits colony formation by primary CML CD34(+) cells ex vivo, including a sample expressing the T315I mutant. These data suggest that targeting BCR-ABL1 with CC mutants may provide a novel alternative strategy for treating patients with resistance to current targeted therapies.
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