Stem cell and kinase activity-independent pathway in resistance of leukaemia to BCR-ABL kinase inhibitors

Authors

Shaoguang Li
Dongguang Li, Edith Cowan University

Document Type

Journal Article

Keywords

BCR-ABL, Ph+ leukaemia, leukaemic stem cells, kinase inhibitors, SRC kinases, drug resistance

Publisher

Blackwell Publishing Ltd

Faculty

Faculty of Computing, Health and Science

School

School of Computer and Information Science

RAS ID

5122

Comments

Li, S., & Li, D. (2007). Stem cell and kinase activity-independent pathway in resistance of leukaemia to BCR-ABL kinase inhibitors. Journal of Cellular and Molecular Medicine, 11(6), 1251. Available here

Abstract

BCR-ABL tyrosine kinase inhibitors, such as imatinib (Gleevec) are highly effective in treating human Philadelphia chromosome-positive (Ph⁺) chronic myeloid leukaemia (CML) in chronic phase but not in terminal acute phase; acquired drug resistance caused mainly by the development of BCR-ABL kinase domain mutations prevents cure of the leukaemia. In addition, imatinib is ineffective in treating Ph⁺ B-cell acute lymphoblastic leukaemia (B-ALL) and CML blast crisis, even in the absence of the kinase domain mutations. This type of drug resistance that is unrelated to BCR-ABL kinase domain mutations is caused by the insensitivity of leukaemic stem cells to kinase inhibitors such as imatinib and dasatinib, and by activation of a newly-identified signalling pathway involving SRC kinases that are independent of BCR-ABL kinase activity for activation. This SRC pathway is essential for leukaemic cells to survive imatinib treatment and for CML transition to lymphoid blast crisis. Apart from BCR-ABL and SRC kinases, stem cell pathways must also be targeted for curative therapy of Ph⁺ leukaemia.

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