CBL

Overview

CBL (Casitas B-lineage lymphoma) encodes a RING domain E3 ubiquitin ligase that negatively regulates receptor tyrosine kinase signaling, including the MAPK pathway. Loss-of-function mutations in CBL can lead to sustained MAPK pathway activation and have been observed in several malignancies, including myeloid neoplasms and cutaneous squamous cell carcinoma (cSCC).

Alterations observed in the corpus

  • Loss-of-function mutation observed in an example cSCC case; associated with increased phospho-MAPK signaling, consistent with the role of CBL in attenuating receptor tyrosine kinase signaling PMID:39091884.
  • Mutated in lung adenocarcinoma WES study (Broad, 183 tumors) PMID:22980975
  • Mutated in ALL (St. Jude WGS/WES, 44 tumors); CBL mutations identified as part of the RAS/PI3K signaling pathway alterations in pediatric acute lymphoblastic leukemia PMID:23334668
  • Somatic mutation in 1 MPN patient across PV/ET/MF cohort in CALR discovery study PMID:24325359
  • Frequent truncating/damaging missense mutations in desmoplastic melanoma with no synonymous mutations detected, consistent with a tumor-suppressor role; enriched in the context of absent BRAF V600E and NRAS Q61K/R PMID:26343386
  • CBL: 7 alterations including hotspot W408R (RING finger), three X410 splice sites, and one homozygous deletion in germ cell tumor cohort PMID:27646943

Cancer types (linked)

  • CSCC: Loss-of-function CBL mutation identified in the AK-to-cSCC evolutionary trajectory; acts as a secondary event potentiating MAPK pathway activation PMID:39091884.

Co-occurrence and mutual exclusivity

Therapeutic relevance

  • Increased phospho-MAPK signaling downstream of CBL loss may sensitize tumors to MAPK pathway inhibition, though this has not been directly tested in cSCC PMID:39091884.

Open questions

  • The prevalence of CBL loss-of-function mutations across cSCC cohorts has not been systematically quantified; the current observation is from a single case study within a larger evolutionary framework.

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:22980975

This page was processed by crosslinker on 2026-05-14. - PMID:23334668

This page was processed by crosslinker on 2026-05-14. - PMID:24325359

This page was processed by crosslinker on 2026-05-14. - PMID:26343386

This page was processed by crosslinker on 2026-05-14. - PMID:27646943

This page was processed by wiki-cli on 2026-05-14.