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Updated: Aug 5, 2026
10:21
Proliferation and Differentiation of Murine Myeloid Precursor 32D/G-CSF-R Cells
Published on: February 21, 2018
[DDX41-mutated myeloid neoplasms]
1Department of Hematology and Medical Oncology, Shinshu University School of Medicine.
Summary
Germline DDX41 variants are a common cause of hereditary myeloid cancers like MDS/AML, especially in men. Early screening is crucial due to risks like post-transplant leukemia.
Area of Science:
- Hematology
- Genetics
- Oncology
Background:
- Germline variants in the DDX41 gene are a significant cause of hereditary predisposition to myeloid malignancies, particularly Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML).
- These variants are frequently observed in MDS with increased blasts and secondary AML, with a prevalence of 3% to 9% across various subtypes.
- Approximately 60% of these germline variants are nonsense or frameshift mutations, often requiring a secondary somatic missense mutation for disease manifestation.
Purpose of the Study:
- To delineate the prevalence, characteristics, and clinical implications of germline DDX41 variants in hereditary myeloid cancers.
- To assess the penetrance and population-specific frequencies of DDX41 mutations.
- To evaluate the challenges in disease stratification and therapeutic strategies for DDX41-mutated MDS/AML.
Main Methods:
- Retrospective analysis of patient data including genetic sequencing and clinical outcomes.
- Population-based frequency assessments across diverse ethnic and geographic cohorts.
- Review of treatment responses to hypomethylating agents and venetoclax.
Main Results:
- DDX41 variant frequency is 2-3 times higher in males; adverse co-mutations (e.g., FLT3, NRAS) are rare.
- Penetrance is low before age 40, reaching approximately 50% by age 90, with consistent estimates across Japanese, UK, and French populations.
- DDX41 variants represent about 80% of known hereditary myeloid predisposition syndromes, posing stratification challenges with standard scoring systems (IPSS-R, IPSS-M).
Conclusions:
- DDX41 is the predominant gene implicated in hereditary myeloid predisposition syndromes, necessitating awareness in clinical practice.
- Hypomethylating agents combined with venetoclax show therapeutic efficacy in DDX41-mutated MDS/AML.
- Presymptomatic screening for DDX41 variants is critical, especially in potential related donors, to prevent post-transplant leukemia.
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