CRTC1/MAML2 gain-of-function interactions with MYC create a gene signature predictive of cancers with CREB–MYC involvement

Abstract

Chimeric oncoproteins created by chromosomal translocations are among the most common genetic mutations associated with tumorigenesis. Malignant mucoepidermoid salivary gland tumors, as well as a growing number of solid epithelial-derived tumors, can arise from a recurrent t (11, 19)(q21;p13.1) translocation that generates an unusual chimeric cAMP response element binding protein (CREB)-regulated transcriptional coactivator 1 (CRTC1)/mastermindlike 2 (MAML2) (C1/M2) oncoprotein comprised of two transcriptional coactivators, the CRTC1 and the NOTCH/RBPJ coactivator MAML2. Accordingly, the C1/M2 oncoprotein induces aberrant expression of CREB and NOTCH target genes. Surprisingly, here we report a gain-of-function activity of the C1/M2 oncoprotein that directs its interactions with myelocytomatosis oncogene (MYC) proteins and the activation of MYC transcription targets, including those involved in cell growth and metabolism, survival, and tumorigenesis. These results were validated in human mucoepidermoid tumor cells that harbor the t (11, 19)(q21;p13.1) translocation and express the C1/M2 oncoprotein. Notably, the C1/M2-MYC interaction is necessary for C1/M2-driven cell transformation, and the C1/M2 transcriptional signature predicts other human malignancies having combined involvement of MYC and CREB. These findings suggest that such gain-of-function properties may also be manifest in other oncoprotein fusions found in human cancer and that agents targeting the C1/M2-MYC interface represent an attractive strategy for the development of effective and safe anticancer therapeutics in tumors harboring the t (11, 19) translocation.

Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma

“…In biphenotypic sinonasal sarcoma, PAX3-MAML3 fusion genes had the same MAML3 breakpoint as in PCC/PGL and were not associated with increased expression of NOTCH target genes (Wang et al, 2014). On the other hand, the CRTC1-MAML2 fusion gene in mucoepidermoid carcinomas did affect NOTCH signaling (Enlund et al., 2004) and also had a gain-of-function interaction with Myc (Amelio et al, 2014), consistent with MYC overexpression in MAML3 fusion-positive PCC/PGLs. Future work may illuminate whether mastermind fusions in other tumor types lead to Wnt signaling pathway upregulation.…”

“…Fusion genes involving mastermind family members have been reported in other tumor types (Amelio et al, 2014; Enlund et al, 2004; Wang et al, 2014). In biphenotypic sinonasal sarcoma, PAX3-MAML3 fusion genes had the same MAML3 breakpoint as in PCC/PGL and were not associated with increased expression of NOTCH target genes (Wang et al, 2014).…”

Whole-Exome Sequencing of Salivary Gland Mucoepidermoid Carcinoma

“…It has been shown that ectopic expression of Mect1-Maml2 may be tumorigenic in rat epithelial cells, and inhibition of the fusion protein using RNA interference can suppress growth in fusion-positive MEC cell lines(40). A recent report suggests that the fusion protein may also interact with Myc and activate Myc transcription targets, including genes involved in cell growth, metabolism, survival, and tumorigenesis(41). These findings, along with lack of significant driver oncogene mutations in MEC, strongly suggest that MECT1-MAML2 translocation may be the main oncogenic driver in this tumor type.…”

Correlation of Crtc1/3-Maml2 fusion status, grade and survival in mucoepidermoid carcinoma

“…Characterization of novel driver mutations and biomarkers could lead to treatment stratification paradigms and targeted therapy options to improve patient survival. As CRTC1 and CRTC3 are involved with cell cycle, and MAML2 is involved with cell differentiation, further analysis of mutations in cell cycle and cell differentiation pathways by next generation sequencing techniques may highlight new, and novel driver mutations in MECs [19–22] . Previous studies have identified some genetic differences between low-grade MECs, and higher grade MECS, including copy number variations in SMAD4 , CDKN2A , DCC , and LYN , all cancer-associated genes [23] .…”