CARD11

Overview

CARD11 is a scaffold protein in the CBM complex that couples BCR signaling to NF-kB activation. Coiled-coil domain mutations produce BTK-independent NF-kB activation and are a recognized mechanism of primary ibrutinib resistance in B-cell lymphomas.

Alterations observed in the corpus

  • Mutated in 6 patients (24%) of the sequenced PCNSL subset in the MSK ibrutinib phase II trial; mutations mapped to the coiled-coil domain PMID:38995739.
  • Identified as recurrently mutated in DLBCL and FL by whole-genome/exome sequencing of non-Hodgkin lymphomas PMID:21796119
  • Identified as a recurrently mutated gene in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing of 55 tumors PMID:22343534
  • Cited as a DLBCL driver gene appearing as rare mutation in multiple myeloma (MM) patients lacking the 11 canonical MM driver mutations; relevant to the somatic-hypermutation signature context in MM PMID:24434212
  • Co-amplified with EGFR on chr 7p as a metastasis-private high-level amplification in one CRC patient (confirmed by FISH) PMID:25164765
  • CARD-domain mutations E24K and D199N disrupt autoinhibition in cutaneous squamous cell carcinoma (29-tumor NGS cohort); CARD11 activation correlated paradoxically with longer PFS PMID:25589618
  • Mutations in 30% of PCNSL cases; one case with high-level amplification at 7p22; identified in genome-wide analysis of 18 PCNSL samples PMID:25991819
  • CARD11 classified as a B-cell activity driver in CLL in a 538-sample WES study, alongside TRAF2 and TRAF3 PMID:26466571
  • Linker-domain mutations p.Ser615Phe and p.Glu626Lys in two Sézary syndrome cases; functionally NFκB- and JNK-activating after TCR stimulation; distinct location from the coiled-coil mutations classical to DLBCL PMID:26551667
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Cancer types (linked)

  • PCNSL — CARD11-mutant PCNSLs had shorter PFS on ibrutinib (median 2.2 vs 5.5 months), consistent with prior reports of CARD11-mediated ibrutinib resistance in B-cell malignancies PMID:38995739.
  • DLBCLNOS — established site of CARD11-mediated BTK-independent NF-kB activation PMID:38995739.

Co-occurrence and mutual exclusivity

Therapeutic relevance

  • Coiled-coil-domain CARD11 mutations mark likely primary resistance to ibrutinib and other BTK inhibitors; patients may require combination strategies bypassing BTK PMID:38995739.

Open questions

  • Whether downstream NF-kB or MALT1 inhibition can rescue response in CARD11-mutant PCNSL PMID:38995739.

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:21796119

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

This page was processed by crosslinker on 2026-05-14. - PMID:24434212

This page was processed by crosslinker on 2026-05-14. - PMID:25164765

This page was processed by crosslinker on 2026-05-14. - PMID:25589618

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

This page was processed by crosslinker on 2026-05-14. - PMID:26466571

This page was processed by crosslinker on 2026-05-14. - PMID:26551667

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

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