NUTM1-Rearranged Neoplasms—A Heterogeneous Group of Primitive Tumors with Expanding Spectrum of Histology and Molecular Alterations—An Updated Review
Igor Shendrik
Round 1
Reviewer 1 Report
Outstanding and comprehensive review. Will be a great help for all pathology practitioners and researchers alike.
Just a minor comment. Please check a slightly conflicting statements on line 66-67 'Conventional chemoradiation therapy is mainly futile, conferring no prognostic advantage15 and line 123 '..radiation at any time point11, and radiation dose > 50 Gy19 have been associated with better survival.' .
Possibly may be resolved by deleting 'conferring no prognostic advantange", which makes the statements more balanced.
line 68 'bromodomain protein inhibitor (BETi)16'
consider full transcription of the acronim as stated in abstract 'bromodomain and extraterminal domain inhibitor (BETi).
line 149
'rhabdoid tumor cells13 or changes mimicking myoepithelial cell neoplasm such'
probably such as would be better.
Author Response
Outstanding and comprehensive review. Will be a great help for all pathology practitioners and researchers alike.
Just a minor comment. Please check a slightly conflicting statements on line 66-67 'Conventional chemoradiation therapy is mainly futile, conferring no prognostic advantage15
Answer: The sentence has been revised accordingly.
and line 123 '..radiation at any time point11, and radiation dose > 50 Gy19 have been associated with better survival.' .
Possibly may be resolved by deleting 'conferring no prognostic advantange", which makes the statements more balanced.
Answer: The sentence has been revised accordingly.
line 68 'bromodomain protein inhibitor (BETi)16'
consider full transcription of the acronim as stated in abstract 'bromodomain and extraterminal domain inhibitor (BETi).
Answer: Corrected.
line 149
'rhabdoid tumor cells13 or changes mimicking myoepithelial cell neoplasm such'
probably such as would be better.
Answer: Corrected.
Reviewer 2 Report
This review is timely, well-structured and the most important literature has been considered, and hence should be of interest to researchers and clinicians working on NUT and NUT Midline Carcinomas.
However, before publication, the authors should pay attention to the points summarized below.
Specific points.
1 – A new concept the authors may want to discuss is the impact of mitochondrial activity and cell metabolism on the stability of BRD4-NUT foci (PMID: 34320364). Indeed, activation of mitochondria activity could change histone acetylation/acylation ratio, especially at H4K5, hence impacting BRD4 interaction with chromatin. An increased BRD4-chromatin interaction dynamics could make BRD4 inhibition by JQ1 more efficient. The conclusion is that a stimulation of mitochondrial activity could potentialize a treatment involving BET bromodomain inhibitors.
2 - Page 5, lane 242: tyrosine cannot be acetylated. The correct sentence should be “BRD4 is an epigenetic reader that can recognize and bind the acetylated LYSINES of histone 3 and 4 through its bromodomain ….”.
3 - Page 5 lane 249: by “hypermethylation” the authors probably mean “HYPERPHOSPHORYLATION”.
4 - Page 6, lane 261: “The fusion protein gains extra functionality that either protein alone does not have”.
Please cite reference 64 after this sentence.
5 - Page 6, lane 275: the sentence “sequester transcription machinery from tumor suppressor gene p53...” is difficult to understand. What the cited refence 64 shows is that sequestration of p300 in the BRD4-NUT foci prevents this HAT from acetylating and hence activating p53 upon a genotoxic assault.
6 - Page 6, lane 305: BRD4 cannot be qualified as a transcription factor. In molecular biology, a transcription factor is a protein that controls the rate of transcription by binding to a specific DNA sequence. BRD4 is a chromatin structure and function regulator and not a transcription factor.
7 - The term “transcription factor” is also inappropriately used elsewhere, for instance in page 8, lane 316. Please pay attention to its use all through the text.
8 - Page 9, lane 359, please replace “rest” by “arrest”.
9 - Page 9, lane 372: “histone modifier” is not a correct term. Here the authors mean molecules that affect histone PTMs.
Author Response
This review is timely, well-structured and the most important literature has been considered, and hence should be of interest to researchers and clinicians working on NUT and NUT Midline Carcinomas.
However, before publication, the authors should pay attention to the points summarized below.
Specific points.
1 – A new concept the authors may want to discuss is the impact of mitochondrial activity and cell metabolism on the stability of BRD4-NUT foci (PMID: 34320364). Indeed, activation of mitochondria activity could change histone acetylation/acylation ratio, especially at H4K5, hence impacting BRD4 interaction with chromatin. An increased BRD4-chromatin interaction dynamics could make BRD4 inhibition by JQ1 more efficient. The conclusion is that a stimulation of mitochondrial activity could potentialize a treatment involving BET bromodomain inhibitors.
Answer: Thank you very much to bringing this important topic to our attention. We added a short paragraph on this (lines 284-8).
2 - Page 5, lane 242: tyrosine cannot be acetylated. The correct sentence should be “BRD4 is an epigenetic reader that can recognize and bind the acetylated LYSINES of histone 3 and 4 through its bromodomain ….”.
Answer: Corrected.
3 - Page 5 lane 249: by “hypermethylation” the authors probably mean “HYPERPHOSPHORYLATION”.
Answer: Corrected.
4 - Page 6, lane 261: “The fusion protein gains extra functionality that either protein alone does not have”.
Please cite reference 64 after this sentence.
Answer: Corrected. Please note that it is now ref#65 as we added one reference following the request of reviewer#3.
5 - Page 6, lane 275: the sentence “sequester transcription machinery from tumor suppressor gene p53...” is difficult to understand. What the cited refence 64 shows is that sequestration of p300 in the BRD4-NUT foci prevents this HAT from acetylating and hence activating p53 upon a genotoxic assault.
Answer: The sentence has been revised accordingly.
6 - Page 6, lane 305: BRD4 cannot be qualified as a transcription factor. In molecular biology, a transcription factor is a protein that controls the rate of transcription by binding to a specific DNA sequence. BRD4 is a chromatin structure and function regulator and not a transcription factor.
Answer: Thank you for this explanation. We corrected this accordingly.
7 - The term “transcription factor” is also inappropriately used elsewhere, for instance in page 8, lane 316. Please pay attention to its use all through the text.
Answer: Thank you for bringing this important issue to our attention. We corrected it throughout the manuscript.
8 - Page 9, lane 359, please replace “rest” by “arrest”.
Answer: Corrected.
9 - Page 9, lane 372: “histone modifier” is not a correct term. Here the authors mean molecules that affect histone PTMs.
Answer: Corrected.
Reviewer 3 Report
I congratulate authors for these review
The topic of this paper is related to a heterogeneous group of tumors sharing a translocation involving the gene NUT1. This is an important paper because it reviews not only the commonest midline site of origin but also the less studied and known other possible origins.
The paper is an exhaustive review that spaces from the genetics of the tumor to the other genes involved in its epigenetic derangement that brings to the malignant phenotype.
Finally, conclusions and references are appropriate to the type of paper.
Line 73: “The incidence and clinical course of NUTM1-rearranged sarcomas are presently unclear due to the small number of described cases.” Please provide references
Author Response
I congratulate authors for these review
The topic of this paper is related to a heterogeneous group of tumors sharing a translocation involving the gene NUT1. This is an important paper because it reviews not only the commonest midline site of origin but also the less studied and known other possible origins.
The paper is an exhaustive review that spaces from the genetics of the tumor to the other genes involved in its epigenetic derangement that brings to the malignant phenotype.
Finally, conclusions and references are appropriate to the type of paper.
Line 73: “The incidence and clinical course of NUTM1-rearranged sarcomas are presently unclear due to the small number of described cases.” Please provide references
Answer: Thank you very much for your favorable comments.
Line 73: The statement has been supported by the reference.
