PONE-D-22-03405Blockade of p38 MAPK overcomes AML stem cell line KG1a resistance to 5-Fluorouridine and the impact on miRNA profilingPLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This quite interesting manuscript by Sabine Matou-Nasri et al. demonstrates that P38 MAPK pathway blockade enhanced KG1α cell sensitivity to 5-Fluorouridine, which was associated with the up-regulation of miR-328-5p and down-regulation of miR-210-5p.

Comment 1: In this research, mostly all the KG1α cells were positive in stem cell marker CD34 and negative in lymphocyte differentiation marker CD38. For the results, the authors should provide statistical diagrams, at least as supplemental materials. However, other studies had shown that a significant number of KG1α cells were not CD34+/CD38-. The proportion of CD34+/CD38- cells in these studies ranged from 17.6%±1.2% to 54.167%±6.57%. Maybe the enrichment of CD34+/CD38- LSCs using magnetic beads could help to find the main gene expression profiling characterizing the chemoresistance potential of AML stem cell.

Comment 2: HL60 is known as chemosensitive AML-M3 cell line. However, 5FUrd is rarely used in the treatment of acute promyelocytic leukemia. Although it is common to select HL60 as the control cell of KG1α, it is not appropriate to use HL60 in the study of 5FUrd.

Comment 3: In the abstract and discussion, the authors wrongly described‘miR-328-3p’ as ‘miR-328-5p’ .

Reviewer #2: The manuscript titled "Blockade of p38MAPK overcomes AML stem cell line KG!a..." by Matou-Nasri S., et al. concerns the drug resistance phenomenon, which often occurs during the treatment of AML patients. The researchers' attention is drawn to AML stem cells due to their high potential for chemoresistance.

The authors of this study showed that targeting p38 MAPK pathway can sensitize drug-resistant AML cells in the KG1a cell line. This drug sensitivity effect was also dependent on miRNA downregulation. The work is done very carefully and shows that by blocking these two signaling pathways, it induces apoptosis in KG1a cells in both extrinsic and intrinsic manner as well as inhibition of the cell proliferation.

Data shown in the manuscript are very solid and convincing, clearly proves that the thesis and conclusions contained in this paper are true and relevant.

In my opinion it should be accepted for publication in PLOS ONE as it is now.

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Reviewer #1: No

Reviewer #2: No

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Blockade of p38 MAPK overcomes AML stem cell line KG1a resistance to 5-Fluorouridine and the impact on miRNA profiling

PONE-D-22-03405R1

Dear Dr. Matou-Nasri,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Jinsong Zhang

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This quite interesting manuscript by Matou-Nasri S. et al. demonstrates that P38 MAPK pathway blockade enhanced KG1α cell sensitivity to 5-Fluorouridine, which was associated with the up-regulation of miR-328-5p and down-regulation of miR-210-5p. The author have critically answered all the reviewers’ questions point to point in the rebuttal letter. After revision, the manuscript meets the publication standard of PLOS ONE.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No