16q23.2

AYGRP,CCA4,CTRCT21,c-MAF

Multiple myeloma (cancer of plasma B cells).

MAF translocations are of poor prognosis.

t(14;16)(q32;q23).

No fusion protein. These translocations lead to the juxtaposition of a strong immunoglobulin enhancer to the MAF promoter leading to its strong ectopic expression.

Large Maf proteins, MAFA, MAFB and MAF/c-MAF, are bona fide oncoproteins as demonstrated in tissue culture, animal models and in human cancer. Their oncogenic activity depends on their ability to act as transcription factors, relies on overexpression and does not require activating mutations (no such mutations have been found in human cancers), although it can be enhanced by point mutation. It is noteworthy that the transforming activity of Maf proteins is context-dependent. It is regulated by post-translational modifications, notably phosphorylation. They can occasionally display tumor suppressor-like activity in specific cellular settings. In embryonic fibroblasts, MAFA displays the strongest transforming activity. Its transforming activity depends on its phosphorylation by GSK3. In human, MAF/c-MAF, MAFB and MAFA genes are translocated to the immunoglobulin heavy chain (IgH) locus in 8-10% of multiple myelomas (MM). These translocations lead to overexpression through a strong enhancer effect without any alteration in their coding sequence. MAF translocations are present in 5% of MM. Beside these translocations, MAF is overexpressed in 50% of MM through an unknown mechanism. MAF overexpression plays a causative role in MM by promoting proliferation through cyclinD2 (CCND2) induction. It also promotes the pathological interactions of bone marrow stroma with cancer cells by enhancing integrin B7 (ITGB7) expression. These pathological cellular interactions lead to increased production of the angiogenic cytokine VEGF. MAF also activates the Ser/Thr AKT activity by inducing the expression of DEPTOR (DEPDC6), an inhibitor of mTORC1 and mTORC2 complexes.
While MM is associated with osteolytic lesions, patients with MAF deregulation show low incidence of bone disease. This observation is correlated with low expression by MAF-expressing myeloma cells of DKK1, a Wnt antagonist associated with bone disease in MM.
Chemical screens have identified glucocorticoids as potential therapeutical agents that target MAF activity through ubiquitin dependent degradation.

Not determined.

MAF has been shown to be overexpressed in 60% of angioimmunoblastic T cell lymphoma. The mechanisms underlying these deregulations are unknown. Although its causative role has not been demonstrated, its deregulation, as in multiple myeloma, is associated to that of CCND2 and ITGB7. MAF has also been found overexpressed in diverse human T cell lymphomas. Accordingly, MAF overexpression in the T cell compartment leads to T cell lymphoma associated with CCND2 and ITGB7 overexpression in transgenic mice.

Congenital cataract

In human, the MAF gene is mutated in congenital cataract that could be associated with microcornea or colomboma. These heterozygote point mutations correspond to residues located in the DNA binding domain and appear to be dominant. They disrupt DNA binding activity by targeting the different conserved basic residues R288P, K297R and R299S. Another mutation in the leucine zipper dimerization domain (K320E) was reported. In support for a role of MAF in congenital cataract, knockout studies in mice have demonstrated an important role of MAF during lens development. Moreover, heterozygote point mutants of murine MAF in its transactivation (D90V) or basic domain (R291Q, corresponding to human residue R294) lead to cataract in mice.