STAP‐2 interacts with and modulates BCR‐ABL‐mediated tumorigenesis

Abstract

In chronic myeloid leukemia (CML), the BCR‐ABL fusion oncoprotein activates multiple pathways involved in cell survival, growth promotion and disease progression. In this report, we show that the signal transducing adaptor protein‐2 (STAP‐2) is involved in BCR‐ABL activity. We demonstrate that STAP‐2 binds to BCR‐ABL, and BCR‐ABL phosphorylates STAP‐2 Tyr250 and the phosphorylated STAP‐2 in turn up‐regulated BCR‐ABL phosphorylation, leading to enhanced activation of downstream signaling molecules including ERK, STAT5, BCL‐xL and BCL‐2. In addition, STAP‐2 interacts with BCR‐ABL to alter chemokine receptor expressions. The interaction between STAP‐2 and BCR‐ABL plays a crucial role in conferring a growth advantage and resistance to imatinib, a BCR‐ABL inhibitor, as well as tumor progression. Notably, mice injected with BCR‐ABL/STAP‐2‐ expressing Ba/F3 cells developed lymph node enlargement and hepatosplenomegaly. Moreover, suppression of STAP‐2 in K562 CML cells resulted in no tumor formation in mice. Our results demonstrate a critical contribution of STAP‐2 in BCR‐ABL activity, and suggest that STAP‐2 might be an important candidate for drug development for patients with CML.