Open AccessStem cell and kinase activity‐independent pathway in resistance of leukaemia to BCR‐ABL kinase inhibitors
Author(s) -
Li Shaoguang,
Li Dongguang
Publication year - 2007
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2007.00108.x
Subject(s) - proto oncogene tyrosine protein kinase src , dasatinib , cancer research , imatinib , tyrosine kinase , abl , tyrosine protein kinase csk , stem cell , kinase , imatinib mesylate , cyclin dependent kinase 9 , protein kinase domain , philadelphia chromosome , biology , sh3 domain , mitogen activated protein kinase kinase , signal transduction , myeloid leukemia , microbiology and biotechnology , protein kinase a , biochemistry , chromosomal translocation , gene , mutant
• Introduction • Ph + leukaemia • Leukaemic stem cells • Identification of CML stem cells in mice • BCR‐ABL kinase inhibitors do not completely eradicate CML stem cells • B‐ALL stem cells and their sensitivity to kinase inhibitors • SRC kinase may impact B‐ALL stem cell functions through activation of the downstream signalling molecule β‐catenin • Activation of SRC kinases by BCR‐ABL is independent of its kinase activity • Role of SRC kinases in the development of B‐ALL • Inhibition BCR‐ABL kinase activity and SRC kinase leads to long‐term survival of B‐ALL mice • Role of SRC kinases in progression of CML to lymphoid blast crisis • Comments and conclusionsAbstract 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.