Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia

Gu, Zhaohui; Churchman, Michelle L.; Roberts, Kathryn G.; Li, Y.; Liu, Y; Harvey, Richard C.; McCastlain, Kelly; Reshmi, SC; Payne-Turner, Debbie; Iacobucci, Ilaria; Shao, Ying; Chen, IM; Valentine, Marcus B.; Pei, Deqing; Mungall, KL; Mungall, A.J.; Ma, Yusanne; Moore, Richard A.; Marra, Marco A.; Stonerock, Eileen; Gastier-Foster, J. M.; Devidas, Meenakshi; Dai, Yunfeng; Wood, Brent L.; Borowitz, Michael J.; Larsen, EE; Maloney, KW; Mattano, LA; Angiolillo, Anne; Salzer, WL; Burke, MJ; Gianni, Francesca; Spinelli, Orietta; Radich, JP; Minden,; Moorman, AV; Patel, Bela; Fielding, AK; Rowe, J. M.; Luger, SM; Bhatia, Ravi; Aldoss, Ibrahim; Forman, SJ; Kohlschmidt, Jessica; Mrózek, Krzysztof; Marcucci, Guido; Cd, Bloomfield; Stock, Wendy; Kornblau, Steven M.; Kantarjian, H.; Konopleva, Marina; Paietta, Elisabeth; Cl, Willman; Loh, Mignon L.; Hunger, SP; Mullighan, C. G.

doi:10.1038/ncomms13331

Cited by 240 publications

(305 citation statements)

References 44 publications

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“…Interestingly, BRD9, while not categorized as a BET protein, contains a single bromodomain and binds the lysine residues of acetylated histones. ACIN1‐NUTM1 fusions have now also been reported on several more occasions in infant and pediatric ALLs . Other NUTM1 fusion partners reported in ALL are IKZF1 , ZNF618 , AFF1 , SLC12A6 , CUX1 , and BPTF …”

Section: Nutm1‐associated Allmentioning

confidence: 89%

“…ACIN1-NUTM1 fusions have now also been reported on several more occasions in infant and pediatric ALLs. 72,[76][77][78][79] Other NUTM1 fusion partners reported in ALL are IKZF1, 76 With a single exception, all of these NUTM1 fusion partners are predicted to associate directly with DNA and/or participate in chromatin remodeling. The exception, solute carrier family 12 member 6 (SLC12A6), also known as K-Cl cotransporter C (KCC3), is a member of the K-Cl cotransporter family.…”

Section: Max Dimerization Protein (Mad)-nutm1 Tumorsmentioning

confidence: 99%

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Emerging entities in NUTM1‐rearranged neoplasms

McEvoy

Fox

Prall

2020

Genes Chromosomes & Cancer

106

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Structural alterations of NUTM1 were originally thought to be restricted to poorly differentiated carcinomas with variable squamous differentiation originating in the midline organs of children and adolescents. Termed NUT carcinomas (NCs), they were defined by a t(15;19) chromosomal rearrangement that was found to result in a BRD4‐NUTM1 gene fusion. However, the use of DNA and RNA‐based next‐generation sequencing has recently revealed a multitude of new NUTM1 fusion partners in a diverse array of neoplasms including sarcoma‐like tumors, poromas, and acute lymphoblastic leukemias (ALLs) that we propose to call NUTM1‐rearranged neoplasms (NRNs). Intriguingly, the nosology of NRNs often correlates with the functional classification of the fusion partner, suggesting different oncogenic mechanisms within each NRN division. Indeed, whereas NCs are characterized by their aggressiveness and intransigence to standard therapeutic measures, the more positive clinical outcomes seen in some sarcoma and ALL NRNs may reflect these mechanistic differences. Here we provide a broad overview of the molecular, nosological, and clinical features in these newly discovered neoplastic entities. We describe how aberrant expression of NUTM1 due to fusion with an N‐terminal DNA/chromatin‐binding protein can generate a potentially powerful chromatin modifier that can give rise to oncogenic transformation in numerous cellular contexts. We also conclude that classification, clinical behavior, and therapeutic options may be best defined by the NUTM1 fusion partner rather than by tumor morphology or immunohistochemical profile.

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Section: Nutm1‐associated Allmentioning

confidence: 89%

Section: Max Dimerization Protein (Mad)-nutm1 Tumorsmentioning

confidence: 99%

Emerging entities in NUTM1‐rearranged neoplasms

McEvoy

Fox

Prall

2020

Genes Chromosomes & Cancer

106

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“…In the other one‐third of cases, several fusion partners of NUTM1 have been reported in the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer (http://cgap.nci.nih.gov/Chromosomes/Mitelman) and recent papers, such as ACIN1, 41, 42, 43 BCOR1, 44 BRD3, 40 BRD9, 41 BPTF, 45 CIC, 46 CUX1, 42 IKZF1, 42, 47 MXD1, 44 NSD3, 48 SLC12A6, 42 ZNF532, 49 and ZNF618. 42 Although MXD1–NUTM1 fusion has been reported in gastric sarcoma, MXD4 has not been previously reported as a fusion partner of NUTM1. Both MXD1 and MXD4 are members of the MAD gene family and regulate MYC , leading to cell growth in differentiating tissues 50.…”

Section: Discussionmentioning

confidence: 99%

Novel MXD4–NUTM1 fusion transcript identified in primary ovarian undifferentiated small round cell sarcoma

Tamura

Nakaoka

Yoshihara

et al. 2018

Genes Chromosomes & Cancer

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Primary ovarian sarcomas are extremely rare tumors, and their genomic and transcriptomic alterations remain to be elucidated. We performed whole exome sequencing of primary tumor and matched normal blood samples derived from one patient with ovarian undifferentiated small round cell sarcoma. We identified 8 nonsynonymous somatic mutations, and all mutations were missense or nonsense changes. Next, we performed RNA sequencing of the tumor sample and identified two in‐frame fusion transcripts: MXD4–NUTM1 and ARL6–POT1. Most NUTM1 exons were retained in the MXD4–NUTM1 fusion transcript, and we confirmed an increase in NUTM1 mRNA and protein expression in tumor tissue. Further genomic and transcriptomic analyses might lead to the development of new therapeutic strategies based on the molecular characteristics of ovarian undifferentiated small round cell sarcoma.

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“…In a subset of malignant solid tumors of uncertain relationship to NC, NUTM1 has been reported to be fused to CIC , BCOR1, MYXD1, MYXD4, or MGA . In fact, emerging NGS studies are revealing that NUTM1 is quite a promiscuous translocation partner, being fused to BRD9 , ACINI , SLC12A6 , ZNF618 , IKZF1 , or BPTF in a variety of leukemias, and CIC in a subset of primitive neuroectodermal tumors (PNET) of the central nervous system.…”

Section: Molecular Geneticsmentioning

confidence: 99%

NUT Carcinoma: Clinicopathologic features, pathogenesis, and treatment

French

2018

Pathology International

165

255

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NUT carcinoma (NC) is a rare, aggressive subtype of squamous cell carcinoma defined by rearrangement of the NUTM1 (aka NUT) gene. NC is driven by NUT‐fusion oncoproteins resulting from chromosomal translocation, most commonly BRD4‐NUT. This is a nearly uniformly lethal cancer affecting patients of all ages, but predominantly teens and young adults. The cell of origin is unknown, but NC most commonly arises within the thorax and head and neck. NC typically consists of sheets of monomorphic primitive round cells that can exhibit focal abrupt squamous differentiation. Diagnosis of NC is easy, and can be established by positive NUT nuclear immunohistochemical staining. Though characterization of the NUTM1‐fusion gene is desirable by molecular analysis, it is not required for the diagnosis. The increasingly widespread availability of the NUT diagnostic test is leading to increasing diagnoses of this vastly underdiagnosed disease. The NUT midline carcinoma registry (http://www.NMCRegistry.org) serves as a central repository that has provided the main source of clinical and outcomes data for NC. Currently there is no effective therapy for NC, however small molecules directly targeting the BRD4 portion of BRD4‐NUT, termed BET bromodomain inhibitors, have shown activity.

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Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia

Cited by 240 publications

References 44 publications

Emerging entities in NUTM1‐rearranged neoplasms

Emerging entities in NUTM1‐rearranged neoplasms

Novel MXD4–NUTM1 fusion transcript identified in primary ovarian undifferentiated small round cell sarcoma

NUT Carcinoma: Clinicopathologic features, pathogenesis, and treatment

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