A new MAFia in cancer

Eychène, Alain; Rocques, Nathalie; Pouponnot, Célio

doi:10.1038/nrc2460

Cited by 187 publications

(230 citation statements)

References 96 publications

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“…40,41 An interesting candidate target gene of these gains is MAFA, an oncogene with transforming properties that is overexpressed in multiple myeloma and a subtype of T-cell lymphoma. 42 We also detected recurrent gains of 8q11.1-q12.2 (harboring the LYN, MOS, and PLAG1 oncogenes) in four high-grade tumors. This is of special interest because we recently showed that gain of a 1.…”

Section: Discussionmentioning

confidence: 71%

Genomic profiles and CRTC1–MAML2 fusion distinguish different subtypes of mucoepidermoid carcinoma

et al. 2013

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Mucoepidermoid carcinoma is the most common salivary gland malignancy, and includes a spectrum of lesions ranging from non-aggressive low-grade tumors to aggressive high-grade tumors. To further characterize this heterogeneous group of tumors we have performed a comprehensive analysis of copy number alterations and CRTC1-MAML2 fusion status in a series of 28 mucoepidermoid carcinomas. The CRTC1-MAML2 fusion was detected by RT-PCR or fluorescence in situ hybridization in 18 of 28 mucoepidermoid carcinomas (64%). All 15 low-grade tumors were fusion-positive whereas only 3 of 13 high-grade tumors were fusion-positive. Highresolution array-based comparative genomic hybridization revealed that fusion-positive tumors had significantly fewer copy number alterations/tumor compared with fusion-negative tumors (1.5 vs 9.5; P ¼ 0.002). Twelve of 18 fusion-positive tumors had normal genomic profiles whereas only 1 out of 10 fusionnegative tumors lacked copy number alterations. The profiles of fusion-positive and fusion-negative tumors were very similar to those of low-and high-grade tumors. Thus, low-grade mucoepidermoid carcinomas had significantly fewer copy number alterations/tumor compared with high-grade mucoepidermoid carcinomas (0.7 vs 8.6; Po0.0001). The most frequent copy number alterations detected were losses of 18q12.2-qter (including the tumor suppressor genes DCC, SMAD4, and GALR1), 9p21.3 (including the tumor suppressor genes CDKN2A/B), 6q22.1-q23.1, and 8pter-p12.1, and gains of 8q24.3 (including the oncogene MAFA), 11q12.3-q13.2, 3q26.1-q28, 19p13.2-p13.11, and 8q11.1-q12.2 (including the oncogenes LYN, MOS, and PLAG1). On the basis of these results we propose that mucoepidermoid carcinoma may be subdivided in (i) low-grade, fusion-positive mucoepidermoid carcinomas with no or few genomic imbalances and favorable prognosis, (ii) high-grade, fusion-positive mucoepidermoid carcinomas with multiple genomic imbalances and unfavorable prognosis, and (iii) a heterogeneous group of high-grade, fusion-negative adenocarcinomas with multiple genomic imbalances and unfavorable outcome. Taken together, our studies indicate that molecular genetic analysis can be a useful adjunct to histologic scoring of mucoepidermoid carcinoma and may lead to development of new clinical guidelines for management of these patients.

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Section: Discussionmentioning

confidence: 71%

Genomic profiles and CRTC1–MAML2 fusion distinguish different subtypes of mucoepidermoid carcinoma

et al. 2013

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“…Mafb is a member of the large Maf family, which encodes leucine-zipper transcription factors (18). Mafb contributes to cell differentiation and organogenesis in a variety of cell types and tissues, including macrophages, the pancreas, and the kidney (19). The current study suggests that Mafb is required for androgen-dependent embryonic urethral masculinization.…”

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confidence: 76%

Sexually dimorphic expression ofMafbregulates masculinization of the embryonic urethral formation

Suzuki

Numata

Suzuki

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Masculinization of external genitalia is an essential process in the formation of the male reproductive system. Prominent characteristics of this masculinization are the organ size and the sexual differentiation of the urethra. Although androgen is a pivotal inducer of the masculinization, the regulatory mechanism under the control of androgen is still unknown. Here, we address this longstanding question about how androgen induces masculinization of the embryonic external genitalia through the identification of the v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (Mafb) gene. Mafb is expressed prominently in the mesenchyme of male genital tubercle (GT), the anlage of external genitalia. MAFB expression is rarely detected in the mesenchyme of female GTs. However, exposure to exogenous androgen induces its mesenchymal expression in female GTs. Furthermore, MAFB expression is prominently down-regulated in male GTs of androgen receptor (Ar) KO mice, indicating that AR signaling is necessary for its expression. It is revealed that Mafb KO male GTs exhibit defective embryonic urethral formation, giving insight into the common human congenital anomaly hypospadias. However, the size of Mafb KO male GTs is similar with that of wild-type males. Moreover, androgen treatment fails to induce urethral masculinization of the GTs in Mafb KO mice. The current results provide evidence that Mafb is an androgen-inducible, sexually dimorphic regulator of embryonic urethral masculinization.Mafb | masculinization | urethra | hypospadias | androgen receptor

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“…3 MAF is a B-ZIP transcription factor that is aberrantly expressed in myeloma by 2 distinct molecular mechanisms. 4 Approximately 10% of primary myelomas bear a MAF translocation that is associated with very high MAF expression. Typically, the MAF translocation breakpoint occurs many kilobases upstream of the MAF transcriptional start site, suggesting that the IgH enhancer elements drive transcription by regulatory elements in the normal MAF promoter.…”

Section: Introductionmentioning

confidence: 99%

“…5 Furthermore, MAF may regulate invasion and metastasis of cancer cells through its activation of the AKT pathway. 4 These studies established MAF as a target for therapeutic intervention in MM but did not provide a ready means to achieve this clinically. In the present study, we hypothesized that MAF transcription might be driven by intracellular signal transduction pathways, downstream of MMSET, that could be inhibited by clinically available small molecules.…”

mentioning

confidence: 99%

A mechanistic rationale for MEK inhibitor therapy in myeloma based on blockade of MAF oncogene expression

Annunziata

Hernandez²,

Davis

et al. 2011

Blood

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Modulating aberrant transcription of oncogenes is a relatively unexplored opportunity in cancer therapeutics. In approximately 10% of multiple myelomas, the initiating oncogenic event is translocation of musculoaponeurotic fibrosarcoma oncogene homolog (MAF), a transcriptional activator of key target genes, including cyclinD2. Our prior work showed that MAF is up-regulated in an additional 30% of multiple myeloma cases. The present study describes a common mechanism inducing MAF transcription in both instances. The IntroductionMultiple myeloma (MM) is a malignancy of plasma cells that is diagnosed in 20 000 people annually in the United States. 1 Current therapy includes high-dose chemotherapy in conjunction with bone marrow transplantation as well as newer agents, such as bortezomib and lenalidomide. 2 Although these treatments extend survival, they often do not achieve lasting cures, providing an impetus to search for novel therapeutic modalities.MM is molecularly heterogeneous, with 7 subgroups defined by gene expression profiling. 3 Four of these subgroups were associated with recurrent translocations in which an oncogene (musculoaponeurotic fibrosarcoma oncogene homolog [MAF]/MAFB, multiple myeloma SET domain [MMSET]/FGFR3, Cyclin D1 or Cyclin D3) is juxtaposed to immunoglobulin heavy chain (IgH) enhancer elements, causing aberrant oncogene expression. Of the 7 subgroups, the MMSET/FGFR3 and MAF subgroups have been associated with inferior overall survival. 3 MAF is a B-ZIP transcription factor that is aberrantly expressed in myeloma by 2 distinct molecular mechanisms. 4 Approximately 10% of primary myelomas bear a MAF translocation that is associated with very high MAF expression. Typically, the MAF translocation breakpoint occurs many kilobases upstream of the MAF transcriptional start site, suggesting that the IgH enhancer elements drive transcription by regulatory elements in the normal MAF promoter. Other myeloma cases lack an MAF translocation but nonetheless express MAF at levels above those in normal plasma cells. 5 In myeloma cell lines overexpressing MAF by either mechanism, interference with MAF function blocked cell proliferation. 5 This essential function of MAF is probably the result, in part, of its transactivation of cyclin D2, a key regulator of the G 1 -S phase transition of the cell cycle. In addition, MAF expression in myeloma cells causes them to adhere more avidly to bone marrow stromal cells, leading to greater vascular endothelial growth factor secretion by stromal cells; transactivation of integrin ␤7 by MAF contributes to these microenvironmental phenotypes. 5 Furthermore, MAF may regulate invasion and metastasis of cancer cells through its activation of the AKT pathway. 4 These studies established MAF as a target for therapeutic intervention in MM but did not provide a ready means to achieve this clinically. In the present study, we hypothesized that MAF transcription might be driven by intracellular signal transduction pathways, downstream of MMSET, that could be inhibited by ...

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A new MAFia in cancer

Cited by 187 publications

References 96 publications

Genomic profiles and CRTC1–MAML2 fusion distinguish different subtypes of mucoepidermoid carcinoma

Genomic profiles and CRTC1–MAML2 fusion distinguish different subtypes of mucoepidermoid carcinoma

Sexually dimorphic expression ofMafbregulates masculinization of the embryonic urethral formation

A mechanistic rationale for MEK inhibitor therapy in myeloma based on blockade of MAF oncogene expression

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