CBL mutations promote activation of PI3K/AKT signaling via LYN kinase
Belizaire, R.; Koochaki, S. H. J.; Udeshi, N.; Vedder, A.; Sun, L.; Svinkina, T.; Hartigan, C.; Stanclift, C.; Schenone, M.; Carr, S. A.; Padron, E.; Ebert, B. L.
Show abstract
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 SignificanceWe 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.
Matching journals
The top 9 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Convergent organization of aberrant MYB complex controls oncogenic gene expression in acute myeloid leukemia 96%
- Expression of modified FcγRI enables myeloid cells to elicit robust tumor-specific cytotoxicity 96%
- Mitochondrial respiration contributes to the interferon gamma response in antigen presenting cells 95%
Similar papers in this journal
Similar papers in this journal
- PHGDH is required for germinal center formation and is a therapeutic target in MYC-driven lymphoma 95%
- Human NK cell deficiency as a result of biallelic mutations in MCM10 95%
- Targeting Specific Kinase Substrates Rescues Increased Colitis Severity Induced by the Crohn's Disease-Linked LRRK2-N2081D Variant 94%
Similar papers in this journal
Similar papers in this journal
- GFI1 cooperates with IKAROS/IKZF1 to activate gene expression in T-cell acute lymphoblastic leukemia 95%
- CHK2 inhibition provides a strategy to suppress hematological toxicity from PARP inhibitors. 94%
- Exquisite Sensitivity to Dual BRG1/BRM ATPase Inhibitors Reveals Broad SWI/SNF Dependencies in Acute Myeloid Leukemia 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.