NUTM1-Rearranged Neoplasia: Understanding an Expanding Family of Aggressive Cancers

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 4547

Special Issue Editors

Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
Interests: NUT carcinoma; pathology; molecular biology; oncology; epigenetics
Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
Interests: NUT carcinoma; phase 1 drug development; CDK4/6 inhibitors; BET inhibitors; novel therapeutics; breast cancer

Special Issue Information

Dear Colleagues, 

NUTM1-rearranged cancers are defined by rearrangement and formation of NUT-fusion oncoproteins. NUT carcinoma, typified by presence of the BRD4-NUTM1 and other NUTM1- fusions, was for years the only known NUTM1-rearranged neoplasm. This changed upon the emergence of next-generation sequencing, which has revealed that cancers with diverse histologies can harbor various NUTM1-fusions. These include sarcomas, leukemias, and cutaneous carcinomas. 

NUT, the protein encoded by NUTM1, normally functions in testes as a sperm maturation factor that recruits p300 to hyperacetylate chromatin prior to nucleosome eviction and chromatin condensation. When fused to BRD4 or other chromatin-interacting factors, NUT pathologically recruits p300 and the fusion serves as a transcriptional activator. In the case of NUT carcinoma, MYC is targeted and upregulated by BRD4-NUT, driving growth and blocking differentiation of the host cell. It is believed that this same general mechanism occurs in other histologies with differing NUT-fusion oncoproteins. 

Though rare, NUT-rearranged cancers are with few exceptions aggressive, NUT carcinoma being one of the most lethal solid tumors in humans. Despite progress in developing targeted inhibitors, there are no effective treatments for many of these cancers, particularly NUT carcinoma, and thus better understanding of the pathogenesis of this group of emerging entities is needed. This Special Issue will highlight the role of NUT-fusions in neoplasia and will cover both basic and translational scientific progress in the field.

Dr. Christopher Alexander French
Dr. Geoffrey I. Shapiro
Guest Editors

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Keywords

  • NUTM1
  • BRD4
  • BRD4-NUTM1
  • NUT carcinoma
  • porocarcinoma
  • sarcoma
  • leukemia
  • bromodomain
  • p300
  • MYC

Published Papers (2 papers)

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Research

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18 pages, 3623 KiB  
Article
Efficacy of Oncolytic Herpes Simplex Virus T-VEC Combined with BET Inhibitors as an Innovative Therapy Approach for NUT Carcinoma
by Paul V. Ohnesorge, Susanne Berchtold, Julia Beil, Simone A. Haas, Irina Smirnow, Andrea Schenk, Christopher A. French, Nhi M. Luong, Yeying Huang, Birgit Fehrenbacher, Martin Schaller and Ulrich M. Lauer
Cancers 2022, 14(11), 2761; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14112761 - 02 Jun 2022
Cited by 4 | Viewed by 2129
Abstract
NUT carcinoma (NC) is an extremely aggressive tumor and current treatment regimens offer patients a median survival of six months only. This article reports on the first in vitro studies using immunovirotherapy as a promising therapy option for NC and its feasible combination [...] Read more.
NUT carcinoma (NC) is an extremely aggressive tumor and current treatment regimens offer patients a median survival of six months only. This article reports on the first in vitro studies using immunovirotherapy as a promising therapy option for NC and its feasible combination with BET inhibitors (iBET). Using NC cell lines harboring the BRD4-NUT fusion protein, the cytotoxicity of oncolytic virus talimogene laherparepvec (T-VEC) and the iBET compounds BI894999 and GSK525762 were assessed in vitro in monotherapeutic and combinatorial approaches. Viral replication, marker gene expression, cell proliferation, and IFN-β dependence of T-VEC efficiency were monitored. T-VEC efficiently infected and replicated in NC cell lines and showed strong cytotoxic effects. This implication could be enhanced by iBET treatment following viral infection. Viral replication was not impaired by iBET treatment. In addition, it was shown that pretreatment of NC cells with IFN-β does impede the replication as well as the cytotoxicity of T-VEC. T-VEC was found to show great potential for patients suffering from NC. Of note, when applied in combination with iBETs, a reinforcing influence was observed, leading to an even stronger anti-tumor effect. These findings suggest combining virotherapy with diverse molecular therapeutics for the treatment of NC. Full article
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Review

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9 pages, 1035 KiB  
Review
NUT Is a Driver of p300-Mediated Histone Hyperacetylation: From Spermatogenesis to Cancer
by Sophie Rousseaux, Nicolas Reynoird and Saadi Khochbin
Cancers 2022, 14(9), 2234; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14092234 - 29 Apr 2022
Cited by 7 | Viewed by 2058
Abstract
In maturing sperm cells, a major genome re-organization takes place, which includes a global increase in the acetylation of histones prior to their replacement by protamines, the latter being responsible for the tight packaging of the male genome. Understanding the function of the [...] Read more.
In maturing sperm cells, a major genome re-organization takes place, which includes a global increase in the acetylation of histones prior to their replacement by protamines, the latter being responsible for the tight packaging of the male genome. Understanding the function of the oncogenic BRD4-NUT fusion protein in NUT carcinoma (NC) cells has proven to be essential in uncovering the mechanisms underlying histone hyperacetylation in spermatogenic cells. Indeed, these studies have revealed the mechanism by which a cooperation between BRD4, a bromodomain factor of the BET family, NUT, a normally testis-specific factor, and the histone acetyltransferase p300, induces the generation of hyperacetylated chromatin domains which are present in NC cells. The generation of Nut ko mice enabled us to demonstrate a genetic interaction between Nut and Brdt, encoding BRDT, a testis-specific BRD4-like factor. Indeed, in spermatogenic cells, NUT and p300 interact, which results in an increased acetylation of histone H4 at both positions K5 and K8. These two positions, when both acetylated, are specifically recognized by the first bromodomain of BRDT, which then mediates the removal of histone and their replacement by protamines. Taken together, these investigations show that the fusion of NUT to BRD4 in NUT Carcinoma cells reconstitutes, in somatic cells, a functional loop, which normally drives histone hyperacetylation and chromatin binding by a BET factor in spermatogenic cells. Full article
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