Abstract
Germline DDX41 variants in myeloid neoplasms (MNs) are not uncommon, and we explored the prevalence and characterized the clinical and pathologic features in a cohort of 3132 unrelated adult MN patients. By targeted next-generation sequencing, we identified 28 patients (20 men and 8 women) with pathogenic germline DDX41 variants who developed acute myeloid leukemia (AML), in which only 3 (11%) had a family history (FH) of MNs. A subacute clinical course of cytopenia (mean duration of 11.2 months, range 0–72 months) prior to the initial AML diagnosis was accompanied by a low blast count (median at 30%, range 20–70%) in hypocellular marrows (93% of all patients), in vast contrast to the typical proliferative subtypes of AML in the elderly. Most patients had a normal karyotype (75%) and acquired a second DDX41 variant (69%). A favorable overall survival (OS) was observed in comparison to that of common subtypes of AML with wild-type DDX41 in age-matched patients. Our study demonstrated that the frequent germline pathogenic DDX41 variants characterized a clinically distinct AML entity. Features characteristic of DDX41-mutated AML include male predominance, often lack of FH, indolent course, low proliferative potential, frequent somatic DDX41 variants, and a favorable OS.
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PL designed the study and drafted the manuscript. TW, WX, WC, DP, GZ, H-YW, MW, and SB collected patients’ clinical and family history, morphologic, cytogenetic, and molecular data. JV and TK examined patients and performed DDX41 germline testing. PL, TW, WX, WC, DP, GZ, H-YW, and SB interpreted and classified all variants by NGS testing. PL, MW, and JLP reviewed the bone marrow examination. All authors reviewed and approved the final manuscript.
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Li, P., White, T., Xie, W. et al. AML with germline DDX41 variants is a clinicopathologically distinct entity with an indolent clinical course and favorable outcome. Leukemia 36, 664–674 (2022). https://doi.org/10.1038/s41375-021-01404-0
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DOI: https://doi.org/10.1038/s41375-021-01404-0
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