DDX10 RNA Helicase: Structure, Function, and Oncogenic Roles Across Solid and Hematologic Tumors

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

DEAD-box (DDX) RNA helicases are important regulators of RNA metabolism and gene expression. The structural and functional characteristics of DDX10 have led to novel roles in solid tumors and hematopoietic malignancies. Furthermore, the paper states that future efforts should focus on elucidating its condition-specific functions, validating its clinical utility, and developing selective inhibitors to overcome its current limitations. This paper is highly interesting. However, the following four points remain unclear. Please provide additional references, hypotheses, or explanations for these points. (1) DDX10 RNA helicase: its structure, function, and oncogenic role in solid tumors and hematologic malignancies remain unclear. (2) How the ATP and RNA moieties structurally interact to regulate the activity of DEAD-box proteins has not yet been fully elucidated. (3) It has been suggested that HIV-1 induces helicase expression for optimal viral replication, but the underlying mechanism remains unclear. (4) In AML, the reciprocal DDX10::NUP98 transcript was also detected. The possibility that this genetic mutation contributes to the development of leukemia remains unclear. (5) DDX10 has not been studied as thoroughly as other RNA helicases.

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have compiled a timely and comprehensive overview of an understudied yet important oncoprotein, effectively highlighting its dual roles in fundamental cell biology and cancer pathogenesis. This review usefully combines disparate literature, particularly on the clinically significant NUP98::DDX10 fusion, and will serve as a valuable resource for the field.

The review needs restructuring and a stronger analytical thesis to move beyond description and provide critical synthesis.

Major Comments:

1. The review lacks a unifying argument. Please introduce a clear analytical thesis in the Abstract and Introduction (e.g., that DDX10 represents a nexus where RNA metabolism, phase separation, and transcriptional regulation converge to drive oncogenesis). Use this thesis to critically frame the evidence presented throughout.
2. The current separation of "Physiological Functions" and "Aberrant Upregulation" creates repetition. Please reorganize. Consider a primary section on DDX10 in Cancer, with logical subsections comparing mechanisms in solid tumors (overexpression, LLPS) and hematologic malignancies (fusions), which will allow for clearer mechanistic contrasts and synthesis. These author’s describe the DDX expression in high-risk Leukemia’s discuss this also (PMID:36738086).
3. The manuscript reports findings but often does not weigh evidence or resolve contradictions. Please provide deeper discussion on: The context-dependent role of DDX10 as an oncogene versus a reported tumor suppressor in ovarian cancer. The intriguing but underexplored link between DDX10, interferon resistance, and improved response to immune checkpoint inhibitors in melanoma.
4. The section on therapeutic targeting is promising but superficial. Please expand the discussion on compound 5o to critically assess its promise and limitations (e.g., specificity, drug-like properties). Furthermore, use the "Future Directions" conclusion to propose concrete, prioritized research questions stemming from the reviewed biology.
5. The valuable Table 1 and Figure 2 are not sufficiently interpreted in the text. Please add a brief analysis of clinical trends in the table (e.g., patient demographics, outcomes). In the narrative, explicitly guide the reader through Figure 2 to explain how the retained protein domains in each fusion isoform dictate functional consequences.

Minor Comments:

1. Correct the typo “Elicase” to “Helicase” and remove the duplicate “Acute myeloid leukemia (AML).”
2. The caption for Figure 2 (lines 317-323) is currently embedded in the main text. This descriptive text should be moved to the figure legend.
3. Please ensure consistent italicization of gene symbols (e.g.,DDX10, NUP98) throughout the manuscript.
4. Some sentences are lengthy or passive. A thorough edit for concise, active language would improve readability (e.g., “DDX10 promotes progression” rather than “DDX10 has been shown to facilitate tumor progression”).

 

 

 

 

 

 

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors carefully addressed my comments