A Critical SH2-Kinase Domain Interaction in BCR-ABL

Chronic myelogenous leukemia (CML) is a clonal proliferation of myeloid cells in the bone marrow that is caused by a t(9;22) chromosomal translocation known as the Philadelphia chromosome. The translocation fuses the breakpoint cluster region (BCR) gene with the Abelson tyrosine kinase (ABL1), producing BCR-ABL, a constitutively active tyrosine kinase sufficient for initiation and maintenance of CML. Tyrosine kinase inhibitors (TKI) that block the activity of BCR-ABL, including the first-line agent imatinib, target the kinase domain. Although these inhibitors often induce remission, development of resistance is a common complication. In a recent article, Grebien and colleagues demonstrate that an intramolecular interaction between the SH2 and tyrosine kinase domains in BCR-ABL is critical for its catalytic activity. Disruption of the SH2-kinase domain interface, by a single amino acid substitution within the ABL SH2 domain, inhibited the activity of BCR-ABL and abolished the development of leukemia both in vitro and in vivo. Furthermore, the disruption blocked downstream signaling pathways critical for CML formation and sensitized drug-resistant BCR-ABL mutants to TKIs. To determine if the SH2-kinase interface could be targeted in trans, the authors developed a high-affinity monobody specific for the ABL SH2 domain. The monobody not only disrupted the SH2-kinase domain interface and inhibited the activity of BCR-ABL in vitro, it also induced apoptosis in primary CML cells. These findings suggest that an intact SH2-kinase domain interaction is necessary and sufficient for BCR-ABL activity. Importantly, targeting of this interface may be a viable therapeutic intervention for CML patients who fail treatment with TKIs.

Grebien F, Hantschel O, Wojcik J, Kaupe I, Kovacic B, Wyrzucki AM, et al. Targeting the SH2-kinase interface in Bcr-Abl inhibits leukemogenesis. Cell 2011;147:306–19.

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