A child with a t(11;19)(q14-21;p12) in a pulmonary mucoepidermoid carcinoma

Stenman, Göran; Pétursdóttir, Vigdís; Mellgren, Gösta; Mark, Joachim

doi:10.1007/s004280050293

Cited by 35 publications

(24 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…20 The chromosomal translocation t (11;19) that results in the oncogenic CREB-regulated transcription coactivator 1-mastermind-like 2 fusion gene CRTC1-MAML2 has been identified in MECs of the salivary glands and lungs. [20][21][22] Overall, our findings and the reported data together suggest that EML4-ALK may be involved in NSCLC subtypes derived from large or proximal airway cells. Most of the patients who had EML4-ALK were primarily nonsmokers (10 never smokers; 2 passive smokers), and the association was statistically significant when all patients were included in the analysis.…”

Section: Eml4-alk In Nonsmall Cell Lung Cancer/wong Et Alsupporting

confidence: 49%

The EML4‐ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild‐type EGFR and KRAS

Wong

Leung

et al. 2009

Cancer

659

441

View full text Add to dashboard Cite

show abstract

Section: Eml4-alk In Nonsmall Cell Lung Cancer/wong Et Alsupporting

confidence: 49%

The EML4‐ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild‐type EGFR and KRAS

Wong

Leung

et al. 2009

Cancer

659

441

View full text Add to dashboard Cite

show abstract

“…In summary, evidence that Mect1-Maml2 is an important oncogene that underlies the development of malignant salivary gland tumors includes the observations that (a) the t(11;19) rearrangement has been detected as the sole cytogenetic abnormality in several primary tumor samples (12,46,47), (b) Mect1-Maml2 can efficiently transform rat epithelial cells in vitro whereas the reciprocal Maml2-Mect1 transcript was not present in primary or derived tumor samples (1), and (c) Mect1-Maml2 is expressed in 75% of all mucoepidermoid cancers tested to date (1, 2, 12). The present study shows that the CREB-binding amino-terminal domain of Mect1/Torc1 is required for transforming activity.…”

Section: Resultsmentioning

confidence: 99%

Mect1-Maml2 Fusion Oncogene Linked to the Aberrant Activation of Cyclic AMP/CREB Regulated Genes

et al. 2005

View full text Add to dashboard Cite

Malignant salivary gland tumors can arise from a t(11;19) translocation that fuses 42 residues from Mect1/Torc1, a cyclic AMP (cAMP)/cAMP-responsive element binding protein (CREB)-dependent transcriptional coactivator, with 982 residues from Maml2, a NOTCH receptor coactivator. To determine if the Mect1-Maml2 fusion oncogene mediates tumorigenicity by disrupting cAMP/CREB signaling, we have generated in-frame deletions within the CREB-binding domain of Mect1/Torc1 for testing transformation activity and have also developed a doxycycline-regulated Mect1-Maml2 mammalian expression vector for global gene expression profiling. We observed that small deletions within the CREB-binding domain completely abolished transforming activity in RK3E epithelial cells. Further, we have shown that the ectopic induction of Mect1-Maml2 in HeLa cells strongly activated the expression of a group of known cAMP/CREBregulated genes. In addition, we detected candidate cAMPresponsive element sites within 100 nucleotides of the transcriptional start sites of other genes activated by Mect1-Maml2 expression. In contrast, we did not observe alterations of known Notch-regulated target genes in these expression array profile experiments. We validated the results by reverse transcription-PCR in transfected HeLa, RK3E, and H2009 lung tumor cells and in mucoepidermoid cancer cells that endogenously express the fusion oncopeptide. Whereas overexpression of components of the cAMP pathway has been associated with a subset of human carcinomas, these data provide a direct genetic link between deregulation of cAMP/ CREB pathways and epithelial tumorigenesis and suggest future therapeutic strategies for this group of salivary gland tumors. (Cancer Res 2005; 65(16): 7137-44)

show abstract

“…These, and other related tumors, are associated with a t(11;19) translocation that generates a chimeric peptide composed of 42 codons from Mect1 exon 1 which is fused in-frame with 981 codons from the carboxyl-terminal exons 2-5 of the Maml2 gene (Tonon et al, 2003;Enlund et al, 2004a;Behboudi et al, 2005). The importance of the t(11;19) translocation in these tumors was suggested by the observation that the t(11;19) rearrangement was the sole cytogenetic alterations in several tumor samples (El-Naggar et al, 1996;Stenman et al, 1998;Martins et al, 2004), by the ability of Mect1-Maml2 to induce foci formation in rat RK3E epithelial cell in vitro (Tonon et al, 2003;Coxon et al, 2005;Wu et al, 2005), and by the detection of Mect1-Maml2 in 50-70% of mucoepidermoid tumors studied to date (Roberts et al, 2003;Tonon et al, 2003;Enlund et al, 2004a, b;Martins et al, 2004). Although the biological role of this fusion oncopepetide in cancer development is still undefined, a current model for Mect1-Maml2-mediated tumorigenesis suggests that the fusion peptide functions to aberrantly activate a set of CREB/cAMP regulated genes (Coxon et al, 2005;Wu et al, 2005).…”

mentioning

confidence: 99%

Sustained expression of Mect1-Maml2 is essential for tumor cell growth in salivary gland cancers carrying the t(11;19) translocation

et al. 2006

View full text Add to dashboard Cite

Mucoepidermoid (MEC) salivary gland tumors arise from a t(11;19) rearrangement which generates a fusion oncogene, Mect1-Maml2, that functions to activate CREB-responsive target genes. To determine if sustained expression of Mect1-Maml2 is required for tumor cell growth, we first showed that ectopic expression of Mect1-Maml2 in rat epithelial RK3E cells is tumorigenic in vivo in nude mice and that excised xenografts continue to express the fusion oncogene. We then generated a hairpin RNAi vector that selectively suppressed the fusion peptide and showed that ectopic expression in either parotid or pulmonary MEC tumor cell lines containing the t(11;19) rearrangement resulted in at least 90% colony growth inhibition. In contrast, single nucleotide changes within this RNAi sequence abolished the ability to suppress Mect1-Maml2 protein and abolished all growth inhibition of these MEC tumor lines. In addition, the RNAi-specific vector had no effect on colony growth of non-MEC tumors including a lung tumor or two other salivary gland cell lines that do not express Mect1-Maml2. We also generated a mutant Mect1-Maml2 expression plasmid that carried silent nucleotide changes within the RNAi target sequence and observed that co-transfection of this mutant, but not wild-type Mect1-Maml2, could partially rescue RNAi growth inhibition in the MEC tumor line. The recent detection of acquired fusion oncogenes in epithelial solid tumors has suggested new possibilities for the diagnosis and therapy of these cancers. Our data show that the 'gain-of-function' activity from aberrant Mect1-Maml2 expression is a candidate therapeutic target for this group of malignant salivary gland tumors.

show abstract

A child with a t(11;19)(q14-21;p12) in a pulmonary mucoepidermoid carcinoma

Cited by 35 publications

References 9 publications

The EML4‐ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild‐type EGFR and KRAS

The EML4‐ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild‐type EGFR and KRAS

Mect1-Maml2 Fusion Oncogene Linked to the Aberrant Activation of Cyclic AMP/CREB Regulated Genes

Sustained expression of Mect1-Maml2 is essential for tumor cell growth in salivary gland cancers carrying the t(11;19) translocation

Contact Info

Product

Resources

About