Analysis of domain-specific function reveals significant plasticity in BCR-ABL signaling

Abstract Discontinuation of the tyrosine kinase inhibitor (TKI) therapy leads to relapse in chronic myeloid leukemia (CML), suggesting that TKIs do not completely eliminate cancer cells. Recently, we showed that TKIs inhibit catalytic activity of BCR-ABL, but do not dissolve the BCR-ABL core complex, consisting of signaling mediators SHC1, GRB2, SOS1, cCBL, SHIP2, p85a, STS1, and CRKL. Here, we examined the contribution of the BCR-ABL structural domains to downstream signaling. Individual deletion of the coiled-coil domain, ABL-binding domain, intrinsically disordered region, and SH3 and SH2 domains downregulated, but not eliminated the BCR-ABL-mediated phosphorylation of STAT1, STAT5, SHC1, SHIP2 and CRKL. Moreover, elimination of the BCR residue Y177 upregulated signaling via the RAS-ERK MAP kinase pathway, possibly through increased BCR-ABL interaction with the SHC1. We demonstrate that removal of individual BCR-ABL domains does not abolish downstream signaling, and may even increase activation of some pathways, such as RAS-ERK. Our data point to significant plasticity in the BCR-ABL signaling, and undermine targeting integrity of the BCR-ABL core complex as an approach to eliminate residual cancer cells in TKI-treated CML.