TBL1XR1

Overview

TBL1XR1 encodes a WD40-repeat protein that is part of the NCoR/SMRT corepressor complex. Recurrent mutations are observed in B-cell lymphomas, including primary CNS lymphoma (PCNSL), where they have emerged as a candidate predictive biomarker for BTK inhibitor response.

Alterations observed in the corpus

  • Missense mutations mapping to the WD40 domains, interpreted as likely loss-of-function; present in 9/25 (36%) of sequenced PCNSLs in the MSK ibrutinib phase II cohort PMID:38995739.
  • WES of 55 DLBCL tumors identified recurrent TBL1XR1 mutations, suggesting disruption of the NCoR/SMRT transcriptional repressor complex in diffuse large B-cell lymphoma PMID:22343534
  • Recurrent 3q26.32 deletion in primary central nervous system lymphoma (PCNSL); identified as a focal CNA in the genomic landscape of PCNSL. PMID:25991819
  • Identified as a chromatin-function Mut-driver in breast cancer; part of the set of seven chromatin-function Mut-drivers mutated in 22.6% of all tumours in the 2,433-tumour METABRIC cohort PMID:27161491.
  • Preferentially mutated in ABC DLBCL PMID:28985567

Cancer types (linked)

  • PCNSL — mutated in ~36% of PCNSLs; in the MSK ibrutinib trial, TBL1XR1-mutant PCNSLs had median PFS of 16.5 months vs 3.1 months in wild-type (log-rank p=0.0075, HR 0.29, 95%CI 0.11–0.76). In an independent 177-patient MSK cohort treated with standard of care, TBL1XR1 status was not prognostic, suggesting the association is predictive of BTK-inhibitor benefit rather than generally prognostic PMID:38995739.

Co-occurrence and mutual exclusivity

Therapeutic relevance

  • Candidate predictive biomarker for durable response to ibrutinib monotherapy in r/r PCNSL; generalization to second-generation BTK inhibitors such as tirabrutinib remains an open question PMID:38995739.

Open questions

  • Mechanism by which WD40-domain LoF sensitizes PCNSL to BTK inhibition is not established PMID:38995739.
  • Whether TBL1XR1-driven benefit generalizes beyond ibrutinib to other BTK inhibitors PMID:38995739.

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:22343534

This page was processed by crosslinker on 2026-05-14. - PMID:25991819

This page was processed by crosslinker on 2026-05-14. - PMID:27161491

This page was processed by wiki-cli on 2026-05-14. - PMID:28985567

This page was processed by wiki-cli on 2026-05-15.