DDX41 – Acute Myeloid Leukemia

Germline heterozygous variants in DDX41 confer an autosomal dominant predisposition to acute myeloid leukemia (PMID:36322930). Affected individuals typically present after age 50 with cytopenias, hypocellular marrows, and low blast counts. Disease onset is characterized by a slow prodrome of thrombocytopenia and anemia, often leading to normal karyotypes at diagnosis. A second somatic DDX41 mutation, most commonly c.1574G>A (p.Arg525His), is acquired in approximately 70% of cases, driving leukemic transformation (PMID:27174803).

Inheritance is autosomal dominant with variable penetrance. Segregation analysis in a familial acute myeloid leukemia kindred demonstrated the same germline DDX41 variant in 5 of 6 siblings, prompting exclusion of affected relatives as stem cell donors (PMID:38255170). Across large cohorts, 346 unrelated patients harboring pathogenic germline DDX41 variants were identified, with 116 confirmed to carry causal variants (PMID:36322930).

The variant spectrum includes loss-of-function alleles—frameshift, start-loss, and splicing mutations—and recurrent missense changes within the helicase domain. The most frequent germline alterations are p.Met1Ile, p.Asp140GlufsTer2, and p.Arg525His, each leading to reduced helicase activity or abnormal spliceosomal incorporation. A sentinel somatic hotspot, c.1574G>A (p.Arg525His), exemplifies dominant-negative perturbation of ATPase function.

Functional studies corroborate a haploinsufficiency model with biallelic inactivation. Murine hematopoietic stem/progenitor cells lacking one Ddx41 allele display defective erythroid and myeloid differentiation with impaired colony formation and embryonic lethality on complete knockout (PMID:35303436). In vitro, the p.Arg525His mutant impairs ATP-dependent RNA-unwinding and preribosomal RNA processing, inducing ribosomopathy-like growth arrest in CD34+ cells (PMID:27174803). Recent work reveals defective R-loop resolution and dysregulated cGAS-STING signaling in DDX41-deficient cells, linking genomic stress to innate immune activation (PMID:38514771).

No substantive conflicting evidence has been reported for DDX41-related AML; penetrance increases with age, and clinical presentation is consistent across populations. Long-term outcomes are favorable relative to de novo AML, with high complete remission rates following standard chemotherapy and improved survival when venetoclax is incorporated.

Overall, the robust genetic and experimental data establish a definitive role for DDX41 germline variants in adult-onset acute myeloid leukemia. Systematic screening for DDX41 mutations in AML patients facilitates risk stratification, informs donor selection for allogeneic transplantation, and supports precision medicine approaches targeting downstream pathways.

Key Take-Home: Germline DDX41 testing should be integrated into AML diagnostic panels to guide familial counseling, donor selection, and tailored therapeutic strategies.

References

• Blood • 2023 • Comprehensive characterization of DDX41-mutated myeloid neoplasms PMID:36322930
• Biomedicines • 2023 • Case Report of a DDX41 Germline Mutation in a Family with Multiple Relatives Suffering from Leukemia PMID:38255170
• Experimental hematology • 2016 • Biological implications of somatic DDX41 p.R525H mutation in acute myeloid leukemia PMID:27174803
• Stem cell reports • 2022 • DDX41 is needed for pre- and postnatal hematopoietic stem cell differentiation in mice PMID:35303436
• Leukemia • 2024 • Impaired binding affinity of YTHDC1 with METTL3/METTL14 results in R-loop accumulation in myelodysplastic neoplasms with DDX41 mutation PMID:38514771

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