Role of the CARMA1/BCL10/MALT1 complex in lymphoid malignancies

Abstract

Purpose of review: The CARMA1/BCL10/MALT1 (CBM) complex is a multimeric signaling complex controlling several important aspects of lymphocyte activation. Gain-of-function mutations in the genes encoding CBM proteins or their upstream regulators are associated with lymphoid malignancies, whereas loss-of-function mutations lead to immunodeficiency. This review reports on recent findings advancing our understanding of how CBM proteins contribute to malignant and nonmalignant hematological diseases in humans.

Recent findings: Somatic gain-of-function mutations of CARMA1 (also known as CARD11), originally described for patients with diffuse large B-cell lymphoma, have recently been identified in patients with acute T-cell leukemia/lymphoma or Sézary syndrome, and in patients with a B-cell lymphoproliferative disorder known as BENTA. Loss-of-function mutations of CARMA1 and MALT1, on the other hand, have been reported to underlie human immunodeficiency. Lately, it has become clear that CBM-dependent signaling promotes lymphomagenesis not only via NF-κB activation, but also via the AP-1 family of transcription factors. The identification of new substrates of the protease MALT1 and the characterization of mice expressing catalytically inactive MALT1 have deepened our understanding of how the CBM complex controls lymphocyte proliferation through promoting MALT1's protease activity.

Summary: The discovery of CARMA1 gain-of-function mutations in T-cell malignancies and BENTA patients, as well as the association of CARMA1 and MALT1 mutations with human immunodeficiency highlight the importance of CBM proteins in the regulation of lymphocyte functions, and suggest that the protease activity of MALT1 might be targeted to treat specific lymphoid malignancies.

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FIGURE 1

Constitutive CBM signaling in B- and T-cell malignancies. Underlying mechanisms include (a) mutations in CD79A or CD79B and CARMA1/CARD11, and self-antigen recognition, (b) self-antigen recognition or mutations upstream of BTK, (c) germline mutations in CARMA1, (d) generation of a MALT1-API2 fusion protein that activates the classical (NF-κB1) and nonclassical (NF-κB2) pathway, (e, f) gain-of function mutations in PLCγ1, PKCβ, or CARMA1, and in frame mutations of the T-cell co-receptor CD28 with ICOS or CTLA-4. In all figure panels, recurrent mutations are indicated with a yellow star. ABC, activated B-cell; ATLL, acute T-cell leukemia/lymphoma; BENTA, B-cell expansion with NF-κB and T-cell anergy; BCR, B-cell receptor; CBM, CARMA1/BCL10/MALT1; CTLA-4, cytotoxic T lymphocyte-associated protein 4; DLBCL, diffuse large B-cell lymphoma; ICOS, inducible costimulator; MALT, mucosa-associated lymphoid tissue; MCL, mantle cell lymphomas; PKC, protein kinase C; TCR, T-cell receptor.

FIGURE 2

Described CARMA1/CARD11 mutations (a) Mutations found in ABC DLBCL and BENTA. An asterisk indicates mutations in DLBCL that were not clearly identified as ABC DLBCL. Amino acid numbers of some CARMA1 mutations [7] have been adjusted to the UniProt sequence. (b) Mutations identified in ATLL and Sézary syndrome; 8% of ATLL cases have a CARMA1 deletion within the linker domain. Mutations that were not functionally tested are indicated in italics. Mutations common to DLBCL and BENTA (a) or common to Sézary syndrome and ATLL (b) are highlighted in blue. ABC, activated B-cell; ATLL, acute T-cell leukemia/lymphoma; BENTA, B-cell expansion with NF-κB and T-cell anergy; CARD, caspase recruitment domain; CC, coiled coil; DLBCL, diffuse large B-cell lymphoma; GUK, guanylate kinase domain; MAGUK, membrane-associated guanylate kinase; PDZ, domain found in the proteins PSD95, Dlg1 and ZO-1; SH3, Src homology-3 domain.