G3BP2-KIT drives leukemia amenable to kinase inhibition in Ph-like ALL

We describe a patient with Ph-like ALL, in which leukemic cells harbored an in-frame fusion between the GTPase-activating protein (SH3 domain)-binding protein 2 (G3BP2) and the KIT proto-oncogene. This resulted in ectopic expression of a chimeric protein retaining the tyrosine kinase domain of KIT in B-ALL cells. Expression of G3BP2-KIT promoted cytokine-independent proliferation of BaF3 and pre-B ARF null cell lines in vitro and leukemia development in vivo. The resulting G3BP2-KIT-expressing leukemias were sensitive to multiple tyrosine kinase inhibitors in vitro, with dasatinib effective in a preclinical mouse models. These results identify KIT rearrangement as a driver oncogenic alteration in leukemia, and provide the rationale for therapeutic targeting with tyrosine kinase inhibitors in KIT-rearranged Ph-like B-ALL.