Mastermind-Like 3 Controls Proliferation and Differentiation in Neuroblastoma

Heynen, Guus J.J.E.; Nevedomskaya, Ekaterina; Palit, Sander; Basheer, Noorjahan Jagalur; Lieftink, Cor; Schlicker, Andreas; Zwart, Wilbert; Bernards, René; Bajpe, Prashanth Kumar

doi:10.1158/1541-7786.mcr-15-0291-t

Cited by 20 publications

(17 citation statements)

References 43 publications

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“…Recently, Heynen and colleagues found that MAML3 overexpression plays a role in retinoic acid resistance in neuroblastoma, a developmentally-related tumor type (Heynen et al., 2016). These authors reported an 828 gene expression signature of MAML3 activation derived from a neuroblastoma cell line transfected with an exon 1 deleted MAML3 overexpression vector compared to the untransfected parental cell line.…”

Section: Resultsmentioning

confidence: 99%

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Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma

Fishbein¹,

Leshchiner²,

Walter³

et al. 2017

Cancer Cell

604

741

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Summary We report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCC/PGLs), a rare tumor type. Multi-platform integration revealed that PCC/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically-mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, NF1). We also discovered fusion genes in PCC/PGL, involving MAML3, BRAF, NGFR and NF1. Integrated analysis classified PCC/PGLs into four molecularly-defined groups: a kinase signaling subtype, a pseudohypoxia subtype, a Wnt-altered subtype, driven by MAML3 and CSDE1, and a cortical admixture subtype. Correlates of metastatic PCC/PGL included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PCC/PGL precision medicine.

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Section: Resultsmentioning

confidence: 99%

“…(C) Expression scores based on published MAML3 signature (Heynen et al, 2016). (See Supplemental Procedures).…”

Section: Figurementioning

confidence: 99%

Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma

Fishbein¹,

Leshchiner²,

Walter³

et al. 2017

Cancer Cell

604

741

View full text Add to dashboard Cite

show abstract

“…Despite the negative correlation between hASH1 and neuron differentiation observed in neuroblastoma patients, future in vivo studies aimed at evaluating the potential prognostic usefulness of hASH1 in predicting the responsiveness of these tumors to RA-based therapies are needed. Although other factors have been described to modulate RA differentiation in neuroblastoma, hASH1 represents a unique target and a possible biomarker for all neuroblastoma, independent of MYCN amplification status (Shah et al, 2014; Cimmino et al, 2015; Heynen et al, 2016). Future studies will focus on defining the mechanism of action of hASH1 during the early phase of RA-differentiation, which may reveal novel cellular targets of importance to retinoid therapy.…”

Section: Discussionmentioning

confidence: 99%

Achaete-Scute Homolog 1 Expression Controls Cellular Differentiation of Neuroblastoma

Kasim

Heß

Scholz

et al. 2016

Front. Mol. Neurosci.

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Neuroblastoma, the major cause of infant cancer deaths, results from fast proliferation of undifferentiated neuroblasts. Treatment of high-risk neuroblastoma includes differentiation with retinoic acid (RA); however, the resistance of many of these tumors to RA-induced differentiation poses a considerable challenge. Human achaete-scute homolog 1 (hASH1) is a proneural basic helix-loop-helix transcription factor essential for neurogenesis and is often upregulated in neuroblastoma. Here, we identified a novel function for hASH1 in regulating the differentiation phenotype of neuroblastoma cells. Global analysis of 986 human neuroblastoma datasets revealed a negative correlation between hASH1 and neuron differentiation that was independent of the N-myc (MYCN) oncogene. Using RA to induce neuron differentiation in two neuroblastoma cell lines displaying high and low levels of hASH1 expression, we confirmed the link between hASH1 expression and the differentiation defective phenotype, which was reversed by silencing hASH1 or by hypoxic preconditioning. We further show that hASH1 suppresses neuronal differentiation by inhibiting transcription at the RA receptor element. Collectively, our data indicate hASH1 to be key for understanding neuroblastoma resistance to differentiation therapy and pave the way for hASH1-targeted therapies for augmenting the response of neuroblastoma to differentiation therapy.

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“…A cluster of Mastermind-like (MAML) genes, including MAML1 , MAML2 , and MAML3 , encodes transcriptional co-activators for various signal pathways such as Notch signaling and tumor suppressor pathway activated in multiple cancers [ 44 ]. Specifically, the MAML3 gene regulates the retinoic acid gene, which inhibits growth of human tumor cells [ 45 ]. We identified four novel genes, KRTAP4-5 , OR2T35 , GPRIN1 , and MRPL18, of unknown function in tumor progression and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Identification of somatic mutations using whole-exome sequencing in Korean patients with acute myeloid leukemia

et al. 2017

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BackgroundAcute myeloid leukemia (AML) is a biologically and clinically heterogeneous cancer of the bone marrow that is characterized by the rapid growth of abnormal myeloid cells.MethodsWe performed a mutational analysis to identify AML somatic mutations using the whole-exome sequencing data of 36 tumor-normal sample pairs from Korean patients with de novo AML. We explored the functional impact of the genes identified in the mutational analyses through an integrated Gene Ontology (GO) and pathway analysis.ResultsA total of 11 genes, including NEFH (p = 6.27 × 10−13 and q = 1.18 × 10−8) and TMPRSS13 (p = 1.40 × 10−10 and q = 1.32 × 10−6), also demonstrated q values less than 0.1 in 36 Korean AML patients. Five out of the 11 novel genes have previously been reported to be associated with other cancers. Two gene mutations, CEBPA (p = 5.22 × 10−5) and ATXN3 (p = 9.75 × 10−4), showed statistical significance exclusively in the M2 and M3 subtypes of the French-American-British classifications, respectively. A total of 501 genes harbored 478 missense, 22 nonsense, 93 frameshift indels, and/or three stop codon deletions and these gene mutations significantly enriched GO terms for signal transduction (GO:0007165, p = 1.77 × 10−3), plasma membrane (GO:0005886, p = 3.07 × 10−4), and scaffold protein binding (GO:0097110, p = 8.65 × 10−4). The mitogen-activated protein kinase (hsa04010, 7.67 × 10−4) was the most enriched Kyoto Encyclopedia of Genes and Genomes pathway.ConclusionsMorphological AML subtypes may in part reflect subtype specific patterns of genomic alterations. Following validation, future studies to evaluate the usefulness of these genes in genetic testing for the early diagnosis and prognostic prediction of AML patients would be worthwhile.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-017-0382-y) contains supplementary material, which is available to authorized users.

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Mastermind-Like 3 Controls Proliferation and Differentiation in Neuroblastoma

Cited by 20 publications

References 43 publications

Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma

Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma

Achaete-Scute Homolog 1 Expression Controls Cellular Differentiation of Neuroblastoma

Identification of somatic mutations using whole-exome sequencing in Korean patients with acute myeloid leukemia

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