CBL mutations promote activation of PI3K/AKT signaling via LYN kinase

CBL encodes an E3 ubiquitin ligase and signaling adaptor that acts downstream of cytokine receptors. Recurrent CBL mutations occur in myeloid malignancies, but the mechanism by which these mutations drive oncogenesis remains incompletely understood. Here we performed a series of studies to define the phosphoproteome, CBL interactome and molecular mechanisms of signaling activation in cells expressing an allelic series of CBL mutants. Our analyses revealed that increased LYN activation and interaction with mutant CBL are key drivers of enhanced PIK3R1 recruitment and downstream PI3K/AKT signaling in CBL -mutant cells. Furthermore, we demonstrated in vitro and in vivo efficacy of LYN inhibition by dasatinib in CBL -mutant cell lines and primary chronic myelomonocytic leukemia cells. Overall, our data provide rationale for exploring the therapeutic potential of LYN inhibition in patients with CBL -mutated myeloid malignancies. Statement of Significance We investigated the oncogenic mechanisms of myeloid malignancy-associated CBL mutations by mass spectrometry-based proteomics and interactomics. Our findings indicate that increased LYN kinase activity in CBL -mutant cells stimulates PI3K/AKT signaling, revealing opportunities for the use of targeted inhibitors in CBL -mutated myeloid malignancies. ### Competing Interest Statement B.L.E. has received research funding from Celgene and Deerfield and serves on the scientific advisory boards for Skyhawk Therapeutics and Exo Therapeutics. The remaining authors declare no potential conflicts of interest.