Pathophysiology of Myelodysplastic Syndromes
Round 1
Reviewer 1 Report
Very well written article
It deserves to be published.
It would certainly benefit if some figures summarising molecules interactions would be created otherwise is very complicate to follow the reading for not MDS expert. For example del5q is difficult to follow without a "map".
Well done!!
Author Response
Reviewer 1
It would certainly benefit if some figures summarising molecules interactions would be created otherwise is very complicate to follow the reading for not MDS expert. For example del5q is difficult to follow without a "map".
Answer: We thank the reviewer for his/her comments. As recommended by this referee, figures have been added, in particular a chromosome map of 5q.
Reviewer 2 Report
Fontenay and Boussaid provide a general overview of the pathophysiological mechanisms involved in MDS, encompassing the topics of hematopoietic/leukemia stem cells and myeloid progenitors’ phenotype, clonal hematopoiesis and chip, genomic landscape of early MDS and secondary AML, aging, epigenomic and immune dysregulation.
Overall, the review is complete and well organized, and many aspects are depicted in detail.
I have few comments
- The characterization of HSC phenotype along with the description of clonal expansion of abnormal clones in LSC and in myeloid progenitor compartments is granular and helpful, however, it would be interesting that authors give an overview of the mechanisms of the possible modes/hypothesis of clonal selection (branching/linear/neutral evolution). Also, although many details have been provided for the role of the immune microenvironment, the authors did not assess/ or did not give their position concerning the role of the stromal microenvironment (stromal cell composition, signaling and angiogenesis eventually important for the crosstalk with the LSC compartment). They could mention also the impact of stromal defects in the context of dysplastic hematopoiesis.
- I suggest adding one or two figures that can help in visualizing the main pathogenic mechanisms involved (Functional implications of mutated genes, epigenetic mechanisms, metabolic pathways, immunological interactions and immune dysfunction).
- Also, speaking of epistasis it could be useful for the reader to see a table with main interactions and genomic frequencies.
- Another aspect to depict could be the associations between specific genotypic/epigenomic/transcriptional disease characteristics with clinical phenotype and potential drug response patterns.
- Some of the statements referring to previous literature are not referenced (ie: line 48, line 103, line 304…)
Author Response
Reviewer 2
Fontenay and Boussaid provide a general overview of the pathophysiological mechanisms involved in MDS, encompassing the topics of hematopoietic/leukemia stem cells and myeloid progenitors’ phenotype, clonal hematopoiesis and chip, genomic landscape of early MDS and secondary AML, aging, epigenomic and immune dysregulation.
Overall, the review is complete and well organized, and many aspects are depicted in detail.
I have few comments
- The characterization of HSC phenotype along with the description of clonal expansion of abnormal clones in LSC and in myeloid progenitor compartments is granular and helpful, however, it would be interesting that authors give an overview of the mechanisms of the possible modes/hypothesis of clonal selection (branching/linear/neutral evolution).
Answer: We thank the reviewer for his/her comments. Details on the mechanisms of clonal selection have been added page 3 lines 87-89 and page lines 110-118.
- Also, although many details have been provided for the role of the immune microenvironment, the authors did not assess/ or did not give their position concerning the role of the stromal microenvironment (stromal cell composition, signaling and angiogenesis eventually important for the crosstalk with the LSC compartment). They could mention also the impact of stromal defects in the context of dysplastic hematopoiesis.
Answer: Comments and references to proof-of-concept articles and sound reviews have been added page 9 lines 353-8.
- I suggest adding one or two figures that can help in visualizing the main pathogenic mechanisms involved (Functional implications of mutated genes, epigenetic mechanisms, metabolic pathways, immunological interactions and immune dysfunction).
Answer: to answer the two referees’ comments, 3 figures have been added that summarize the general pathophysiology (figure 1), the del(5q) syndrome pathophysiology (figure 2) and the consequences of mis-splicing (figure 3)
- Also, speaking of epistasis it could be useful for the reader to see a table with main interactions and genomic frequencies.
Answer : a table has been generated (table 1)
- Another aspect to depict could be the associations between specific genotypic/epigenomic/transcriptional disease characteristics with clinical phenotype and potential drug response patterns.
Answer: this aspect will be depicted in other articles of the current series.
- Some of the statements referring to previous literature are not referenced (ie: line 48, line 103, line 304…)
Answer: References have been Added.
