Chronic myeloid leukaemia (CML) and B-cell acute lymphoblastic leukaemia (B-ALL) are both caused by the BCR – ABL1 oncogene. However, although the ABL tyrosine-kinase inhibitor imatinib (Glivec) is efficacious in chronic-phase CML, it has little effect in BCR–ABL1-positive B-ALL. Yiguo Hu et al. now show that this is because B-ALL — unlike CML — also relies on activation of SRC kinases for its development, and that a combination of imatinib and a SRC-kinase inhibitor is effective in this disease.

BCR–ABL1 activates SRC kinases in myeloid cells — from which CML is derived — and Hu et al. showed that it also activates SRC kinases in pre-B-lymphoid cells — from which B-ALL is derived. There are eight SRC kinases expressed in haematopoietic cells, but only three — Lyn, Fgr and Hck — were more prominently activated in Bcr–Abl1-induced B-ALL mouse cells, when compared with normal peripheral-blood leukocytes from control mice.

So, are LYN, FGR and HCK involved in leukemogenesis by BCR–ABL1? The authors had previously developed two mouse models, involving the manipulation of Bcr-Abl1-transduced bone marrow such that mice develop either CML or B-ALL. Triple knockout of Lyn, Fgr and Hck in these two mouse models showed that these SRC kinases are required for development of B-ALL, but not CML. Knocking out only one or two of the three SRC kinases showed that a combination of two SRC kinases, but not all three, was required for induction of B-ALL by Bcr–Abl1. So, Lyn, Fgr and Hck must have overlapping or partially redundant functions in the Bcr–Abl1 signalling pathway in mouse B-lymphoid cells.

The authors then tested whether an inhibitor of SRC kinases would be effective alone or in combination with imatinib to treat B-ALL. The SRC kinase inhibitor CGP76030 selectively inhibited Lyn, Fgr and Hck in Bcr–Abl1-positive B-cell or B-ALL mouse cell lines and also inhibited growth and survival of these cells. Mice treated for Bcr–Abl1-induced B-ALL with imatinib or CGP76030 alone showed increased survival, and treatment with both drugs in combination was even more effective. Inhibition of Bcr–Abl1 by imatinib and inhibition of SRC kinases by CGP76030 in leukaemia cells isolated from these mice was confirmed. By contrast, CGP76030 did not improve survival of mice with Bcr–Abl1-induced CML compared with treatment with imatinib alone.

Further understanding of the signalling pathways involved in the transition between chronic and acute phases of leukaemia will help the development of effective combination therapies.