The Genetic and Epigenetic Alterations of Plasmablastic Lymphoma: A Narrative Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

• I suggest slightly changing the title of the manuscript: “The genetic and epigenetic alteration of plasmablastic lymphoma”.
• The abstract should be rewritten. Almost all of the current abstract is background. The appropriate abstract consists of one one-sentence background, one sentence aim of the review, and results (preferably numerical results) from previous papers.
• My main question is whether this manuscript is novel since there are plenty of reviews and reports published in this area.
• Epigenetic modification pathways in PBL have been discussed very little. The authors should describe DNA methylation in the promoter region, histone profile, and miRNA patterns in healthy and PBL persons.

Author Response

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Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

Dear Authors, 

Thank you very much for the review scientific work done.

PBL is an uncommon form of non-Hodgkin lymphoma characterized by a poor prognosis and a lack of clarity regarding the most effective treatment strategies. Due to its rarity, there is no established standard of care, and current chemotherapy regimens often fall short of achieving a cure for patients. The overall prognosis for PBL is generally unfavorable, with an approximate 3 to 5-year survival rate of around 40%. There is a scarcity of prospective evidence, as most available information comes from case reports and limited retrospective studies. Additionally, the literature does not consistently identify risk factors for survival or how these factors might guide treatment decisions, often presenting conflicting findings.

Covering such an important issue in the form of a review paper does not raise questions regarding the relevance and validity of the research.  The manuscript is well organized, structured, and has a logically consistent narrative. An illustrative demonstration (presented Figures) of the aggregate information allows the idea being presented to be easily perceived in a summary form.

Obviously, it is impossible to cover all aspects in one article, since this is not a book. However, I decided to kindly ask Authors to consider some of the issues that I find important.

1) Is it possible to provide a general prognosis for the survival rate of patients, including risk factors for development, parametric distributions (gender, age, past medical history, etc.)

2) What are the characteristics of the course of the disease PBL with damage to the central nervous system and the receipt of appropriate prevention?

3) Is there a statistical analysis of palliative chemotherapy as a therapeutic strategy with a certain remission rate?

Author Response

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Reviewer 3 Report

Comments and Suggestions for Authors

1. The study title can be improved for clarity. Please also clearly indicate that this is a narrative review.

2. Much of the content is derivative of earlier reviews, and recent developments (e.g., from high-throughput sequencing, chromatin accessibility assays, or integrated multi-omics) are only superficially addressed or omitted altogether. The authors should clearly define what has changed in the understanding of PBL genetics and epigenetics since previous reviews.

3. Although WGS, RNA-seq, and miRNA sequencing are mentioned, the discussion remains superficial. There is no discussion of single-cell transcriptomics or spatial omics, which are increasingly relevant today.

4. Given that several of the therapeutic strategies are based on anecdotal or case reports (e.g., BCMA CAR-T, PD-1 inhibitors), suggest to structure the therapeutic discussion into preclinical, early clinical trials, and approved approaches, with clear qualifiers about evidence quality.

5. Despite claiming an epigenetic focus, the discussion is largely limited to a few methylation and histone marks, with little mention of epigenetic therapy trials or chromatin accessibility (e.g., ATAC-seq data).

6. On the whole, the narrative lacks a coherent flow. Historical context, molecular features, clinical correlations, and therapeutic strategies are not well integrated. It would be better to reorganize the entire manuscript with a clearer structure, e.g., introduction, pathogenesis, genetic alterations, epigenetic mechanisms, clinical relevance (prognosis, diagnosis), and therapeutic implications. Avoid repetition (e.g., MYC and TP53 are reintroduced multiple times without added value) and ensure each section logically builds on the preceding one.

7. Reading this article, some sections, particularly the historical timelines (Sections 6.1–6.7), are overly descriptive and some parts are redundant.

8. Compared to classical reviews in the field, this manuscript cites a relatively small number of primary research articles. This limits the depth and breadth of the synthesis. The discussion lacks integration across studies or comparative analyses of findings (e.g., how findings in EBV-positive vs. negative cases differ; implications of MYC vs. PRDM1 alterations). The authors should significantly expand their literature base and improve synthesis by drawing meaningful comparisons across studies.

9. To increase the appeal of this review, please look at designing effective visuals (e.g., summary tables, diagrams of signaling pathways, mutation frequency plots), which would enhance impact and clarity.

10. Please do a close edit for language, grammar and style. For example, “Studies has concentrated…” should be “Studies have concentrated…” 

Comments on the Quality of English Language

Moderate edits required.

Author Response

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Author Response File: Author Response.docx

Reviewer 4 Report

Comments and Suggestions for Authors

Bibas et al. thoroughly reviewed the research on genetic and epigenetic characteristics of plasmablastic lymphoma and detailed the molecular similarities and differences among PBL versus multiple myeloma and diffuse large B-cell lymphoma. They also described the importance of HIV and EBV infection in these diseases, and the current and the innovated therapeutic strategies of PBL guided by the genetic and molecular findings. Although some parts of the manuscript seem to be repetitive, overall, it is informative and easy to read. Most of the illustrations are helpful and precise. However, a few illustrations can be improved to increase readability and significance, and authors should cite the figures in the text which can help readers to follow through.

 

1. Please cite all figures in the appropriate locations in the text (same way as supplemental figures). Many figures are nicely illustrated and can help readers to follow the text greatly, however, I often find them in the much later pages or paragraphs and wish I have seen them earlier.
2. Lines 33-44, please also include the clinical symptoms that may lead to confused/differential diagnosis among PBL, DLBCL, and MM.
3. In the abstract, authors stated that studies have demonstrated a significant association between HIV and the development of the disease. However, there is no in-depth discussion about how HIV causes the development of PBL in the manuscript. The information about HIV in PBL is scattered throughout the manuscript and the information provided is vague. Is it mainly due to immunosuppression and the reactivation of EBV by HIV infection? How about people living with HIV (PLWH) who are no longer immunosuppressed?
4. Line 50 please explain why cART/HARRT enhanced survival rates (assuming HIV+ patients with PBL also received traditional PBL therapy). Is it due to the decrease of EBV reactivation?
5. Lines 81-89 (editorial) please use non-bold font.
6. Lines 185-192 authors stated that specific miRNA expression in PBL is associated with EBV and HIV infection. Authors listed a miRNA example for EBV. Please also list an example of miRNA in PBL that is related to HIV.
7. Figure 6. How about adding PD-L1 in EBV+ PBL?
8. Figure 7 is somehow hard to follow. Please use a flow chart with “yes” and “no” to help go through the path.
9. Lines 303-306 Please rewrite this paragraph and provide more description. Please spell out MMSET and describe the outcome of H3K36me2 alteration in PBL.
10. Table 1 (Editorial) is a very informative table and provides lots of information. However, many words got cutoff, and it is not well arranged. Authors (editors) should either re-arrange the table and/or reverse the column/row to make it more readable. This table should also be cited at multiple places in the manuscript for readers to understand and compare the differences along the way.
11. Lines 389-398 authors should explain why CHOP and EPOCH have limited success treating PBL based on the molecular, genetics, and epigenetics differences outlined in this manuscript.
12. In Future Directions and Conclusions, authors should describe the most feasible and useful clinical diagnostic methods that should be used based on the genetic and epigenetic findings to help standardize the diagnostic strategies. Are CD20 and plasma cell markers still used for diagnosis? What tests or markers should be included?

Author Response

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Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have revised their manuscript deeply. However, it would be nice if they could add some data to enrich their manuscript before acceptance.

• The authors described the epigenetic modification in the diagnosis of PBL. It would be beneficial if they search and prepare a section and table for epigenetic drugs (if available) to treat PBL, MM, and DLBCL. Please indicate whether these drugs are FDA-approved or not (under clinical trials).
• It would be beneficial to add a section discussing whether PBL can be proliferated or spread by exosomes and microRNAs.
• I recommend improving all of the figures. Some text within the figures cannot be read (like Fig. 1 and Fig. 3). The description of the table should be at the top of the table, not the bottom of it.

Author Response

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Reviewer 3 Report

Comments and Suggestions for Authors

I am fine with this.

Comments on the Quality of English Language

Moderate edits needed still for clarity.

Author Response

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Author Response File: Author Response.docx