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December 8, 2025BloodOpen Access

Loss-of-function alterations in TRAF3 drive BTK/PLCG2-independent ibrutinib resistance in CLL

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Authors

BKBhavna KumarCUChingiz Underbayev

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Overview

Clinical analysis reveals TRAF3 loss contributes to ibrutinib resistance in CLL, suggesting new therapy targets.

Key Points

  • This research aims to identify mechanisms of ibrutinib resistance in chronic lymphocytic leukemia (CLL).
  • Analyzed 84 patients with CLL who underwent treatment with ibrutinib.
  • Performed whole-exome sequencing on PB samples from patients with progressive CLL.
  • Investigated TRAF3 mutations and their impact on ibrutinib sensitivity using isogenic cell lines.
  • 39 of 84 patients (46.4%) developed progressive disease during treatment.
  • Identified biallelic inactivation of TRAF3 mutations in two patients during progression.
  • TRAF3 knockout (KO) cells showed >50% viability at all ibrutinib concentrations tested, highlighting resistance.

Cite This Study

Kumar et al. (2025) studied this question.

synapsesocial.com/papers/693624d44fa91c937236d008https://doi.org/10.1182/blood-2025-434
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1Clonal architecture and growth dynamics of ibrutinib-resistant CLL: Oligoclonal BTK/PLCG2 mutations and emerging non-BTK/PLCG2 drivers2025 · 1 citations
  2. 2Acquired Bruton's tyrosine kinase mutations in patients treated on the ibrutinib and rituximab, ibrutinib alone, and ibrutinib and venetoclax arms of the national multi-centre Phase III FLAIR study in previously untreated CLL patients2025 · 3 citations
  3. 3Genomic profiling in CLL patients after BTK inhibitor progression identifies enrichment of mutations in MAPK pathway and epigenetic regulators2025
  4. 4Systematic molecular profiling to identify determinants of response to ibrutinib2025
  5. 5Genomic assessment of acquired mutations in participants with CLL/SLL treated with nemtabrutinib in the Phase 2 bellwave-003 study2025 · 1 citations