Decoding DDX41: Clinical impact of germline and somatic mutations in 77 high-risk myeloid neoplasm patients

作者：Talha Badar, Mahesh Kumar, Yael Kusne, Terra Lasho, James M. Foran, Hemant S. Murthy, Mohamed A. Kharfan‐Dabaja, Timothy M. Chlon, Naseema Gangat, Hassan B. Alkhateeb, Abhishek A. Mangaonkar, Rong He, David S. Viswanatha, Jennifer Jiang, Yao‐Shan Fan, Alejandro Ferrer, Mark R. Litzow, Aref Al‐Kali, Mrinal M. Patnaik · 发表于：Blood · 年份：2025 · DOI：10.1182/blood-2025-1442 · 被引用次数：1 · 研究领域：Acute Myeloid Leukemia Research、Genomics and Rare Diseases、Blood disorders and treatments

Abstract Introduction: DDX41 (DEAD-box helicase 41) mutations (mt) represent the most prevalent germline predisposition syndrome (GPS) in adult patients (pts) with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). This molecular subtype is typically associated with late-onset disease, runs an indolent clinical course, with a relative absence of high-risk co-mutations. While several retrospective studies have reported favorable responses to venetoclax (VEN)-based therapies, anecdotal observations suggest variable outcomes. We aimed to evaluate the clinical characteristics and treatment outcomes of patients with DDX41-mt MDS/AML treated at the Mayo Clinic. Methods: We conducted a retrospective study of pts diagnosed with DDX41-mt germline predisposition syndrome with concurrent myeloid neoplasms at our institution. Germline testing was conducted under an IRB approved protocol (Mayo Clinic IRB# 16-004173; clinical-trials gov. Identifier: NCT02958462). Of 198 pts with DDX41-mt myeloid neoplasms, 77 had high-risk disease—43 with MDS with increased blasts (MDS-IB1, n = 11; IB2, n = 32) and 34 with AML (WHO 2022). We assessed how clinical, and disease features influenced outcomes in this subgroup. Among these pts, 69 (90%) pts had likely pathogenic/pathogenic variant (DDX41path) variants and 8 (10%) pts had variant of undetermined significance (DDX41VUS) according to variant classification criteria from the American College of Medical Genetics/ the Association of Med...