The association between BCR–ABL1 expression and chronic myelogenous leukaemia (CML) has been well documented, but there has been debate over the mechanisms by which this chromosome-translocation product mediates cell transformation. In Nature Medicine, Andrzej Ptasznik et al. report that one of these is likely to include the ability of BCR–ABL1 to interact with the tyrosine kinase LYN to promote cell survival.

Leukaemia cells that express BCR–ABL1 are resistant to apoptotic stimuli, and are therefore resistant to standard chemotherapy. Although patients with CML in its chronic stages can be treated by allogeneic stem-cell transplantation or imatinib (Glivec), this disease becomes more difficult to treat once it reaches the blast crisis stage, during which the leukaemic cells become drug resistant and more aggressive.

BCR–ABL1 interacts with several cell signalling proteins to alter a range of cellular functions. One of its downstream effectors, the SRC family member LYN, becomes activated during the blast crisis stage of CML. It could therefore be an important therapeutic target for patients with late-stage disease.

Using short interfering RNA (siRNA), Ptasznik et al. showed that LYN expression could be inhibited by up to 95% in a BCR–ABL1-positive myeloid cell line, in normal haematopoietic cells and also in primary lymphoid and myeloid CML blast crisis cells. Whereas this loss of LYN had no effect on normal cells, the tumour cell types underwent a rapid and massive induction of apoptosis. Primary leukaemia cells derived from both imatinib-resistant and non-resistant patients with CML in the blast crisis stage were particularly sensitive to LYN ablation — over 90% of cells underwent apoptosis. Leukaemia cells from patients in myeloid blast crisis were less sensitive, as their viability was reduced by about 50%.

This study is the first to use siRNA to validate therapeutic targets in primary leukaemia cells, and the authors suggest that this approach might also be developed for therapeutic use. Most importantly, the findings establish LYN as a key target for treating patients with blast crisis stage CML.