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

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.

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.

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.