Molecular Complexity of MDS and AML with Aberrations of Chromosome 7

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors evaluated aberrations of chromosome 7 in patients with MDS and AML in an interesting and well written manuscript and i have the following concerns:

1. Does treatment differ among monosomy 7 (del 7q) among MDS, AML or AML patients after an initial MDS diagnosis? Please provide a table stating the therapeutic approaches and answer that in the discussion.
2. Does laboratory diagnosis of monosomy 7 (del 7q) evaluating the karyotypic lesions differ between MDS and AML? Are there differences regarding chromosome 7 abnormalities between MDS and AML? For example, are there other types of chromosomic 7 lesions observed in MDS compared to AML?
3. The authors make a comparison in the discussion between IC and VEN/HMA as follows: Two induction therapies were available for these patients, one based on intensive chemotherapy (IC) and the other on hypomethylating agent (HMA) plus venetoclax (VEN). It is unclear in these patients whether IC is superior to HMA+VEN. A recent retrospective study reported the results of the analysis of 228 AML patients treated with induction therapy based on IC (38% of patients) or HMA+VEN (62% of patients). 

Since IC is given in fit patients, while HMA+VEN in patients unfit for intensive chemo, do the compared groups differ in age and sex? HMA+VEN is not approved in fit AML patients yet in first line. A direct comparison would make sense if BOTH the regimens could be applied (and approved) for fit AML patients. What is your answer in the discussion?

Author Response

1. Differences in the therapy of MDS and primary and secondary AMLs with chromosome 7 abnormalities are now discussed in the text and summarized in a Table.
2. The laboratory diagnosis of chromosome 7 abnormalities is now discussed in the newly added Section 2. In this section is discussed also the possible occurrence of different chromosome 7 abnormalities in MDS and in AML.
3. It is now more appropriately analyzed and discussed the comparison between IC and VEN/HMA treatment in AML patients.

Reviewer 2 Report

Comments and Suggestions for Authors

The work by Testa, Pelosi and Castelli presents a review of the current understanding of the genomic alterations of chromosome 7 in myeloid neoplasia. Specifically, the authors reviewed the role of partial or complete chromosome 7 deletions and the impacted genes and pathways in the pathogenesis of myelodysplasia (MDS) or acute myeloid leukemia (AML). They also discussed the consequence of chromosome 7 deletion on the treatment response and prognosis.

 

Comments and Suggestions

1. Figure 1 and 2, the schematic representation could be enhanced by (a) adding the impacted pathway(s) where GATA2 or SMAD9(L) are involved. This way, the molecular genetics (i.e. the downstream genes that gene deletion hits) could be better illustrated; (b) providing some comparison between the two gene deficiencies in order to cast light on the differences in the pathogenesis of MDS and pediatric AML.
2. Figure 4, the mutations could be better represented by karyotype pictures where the relative positions as well as the distances of the genes and structural rearrangements are shown. This would help to better understand the impact of the mutations on chromosome 7.
3. Section 4 “Pathogenesis of myeloid neoplasia with chromosome 7 abnormalities”. It would be better if the authors could place chromosome 7 abnormalities in a broader context of the pathogenesis of myeloid neoplasia. For instance, how do chromosome 7 partial or complete deletions interact with other common mutations in MDS/AML that could influence disease progression and therapeutic response?
4. Section 5 “Therapy of myeloid neoplasms with chromosome 7 abnormalities”. The authors could discuss more on how the presence of chromosome 7 abnormalities could influence the decision of treatment strategies.

Author Response

1. The pathogenetic mechanisms and the possible target gens involved n the development op a pathologic hematopoietic phenotype and of MDS and AML in germline GATA2 deficiency and SAMD9 synsromes are now discussed. The Fig.1 was modified, including now a box analyzing the pathogenic mechanisms. The analysis of these pathogenic mechanisms shows the existence of remarkable differences observed in GATA2 deficiency syndromes and SAMDF9 syndromes. A common element observed in these two different germline syndromes is the occurrence of partial or total deletions of chromosome 7, an event that predisposes to the development of myeloid neoplasia.
2. Deletions and structural rearrangements are now discussed in the text and a physical map of the chromosome 7, with indication of the main genes, is now reported in Fig.1.
3. In the section 4, in the analysis of pathogenesis of myeloid neoplasia with chromosome 7 abnormalities, it is now discussed in a broder context the role of chromosome 7 abnormalities and the significance of their association with different co-mutations.
4. It is now discussed in the Section 5 as the detection of chromosome 7 abnormalities could influence therapeutic choices.

Reviewer 3 Report

Comments and Suggestions for Authors

This is very well written extensive review paper reporting clinical significance and particularities of chromosome 7 lesions in myeloid malignancies. I find this very useful for everyday practice. I have only minor grammar comments, but probably important ones:

• there are several places in the manuscript where samd9 is written as smad9, also setbp1 written as sertbp1. Inv(3)/t(3;3) written wrongly on first mention. Please correct and double check throughout the paper for accurate naming of other involved genes.
• Lines 281 and 281, there are some duplicate word sequences
• Multiple small grammar and typing errors

Author Response

 

1. Typing errors concerning naming of genes have been now corrected.
2. Lines 281, duplicated word sequences were deleted.
3. Small grammar and typing errors have been corrected.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I have no further concerns. 

Author Response

 

OK

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have revised the manuscript and addressed most of my concerns. I only have one minor suggestion. The current Figure 2 and 3 are unsatisfactory—each contains five points (i.e. boxes) but between them there is no connection. In fact, we don't assume connections between clinical, molecular and hematological features. Therefore, the best way of representation should be a table to list these points (succinctly as some are very wordy) as rows/columns. Alternatively, the two figures can be simply left out—the main text is well enough.

Author Response

 Figures 2 and 3 have been deleted, as suggested