Sickle cell disease is associated with early-onset clonal hematopoiesis involving DNA damage response pathway mutations

作者：Lachelle D. Weeks, Courtney D. Fitzhugh, Sam Pollock, Miriam A. Osei, Micah Rickles-Young, H. Moses Murdock, Megan Townsend, Christopher W. Reilly, Carla Luana Dinardo, Éster Cerdeira Sabino, Mark Fleharty, Matthew DeFelice, Azeet Narayan, Donna Neuberg, Robert Redd, Lakshmanan Krishnamurti, David A. Williams, Pablo Bartolucci, Carrie Cibulskis, Julia Smith, Milena Batchvarova, Nancy Asomaning, Brian Custer, Kolapo Oyebola, Carlo Brugnara, Russell E. Ware, Vivien Sheehan, Jeffrey Glassberg, Shannon Kelly, Swee Lay Thein, Allison E. Ashley‐Koch, Marilyn J. Telen, Guillaume Lettre, Niall J. Lennon, R. Coleman Lindsley · 发表于：Blood · 年份：2025 · DOI：10.1182/blood-2025-8 · 被引用次数：4 · 研究领域：Hemoglobinopathies and Related Disorders、Acute Myeloid Leukemia Research、Genomics and Rare Diseases

Abstract Background: Individuals with sickle cell disease (SCD) face an elevated risk of myeloid leukemias. Recently, myelodysplastic syndrome and acute myeloid leukemia have emerged as complications of curative SCD therapies, including gene therapy and allogeneic hematopoietic cell transplantation (HCT). Leukemias arising in SCD have been reported to harbor somatic TP53 mutations, and post-HCT TP53-mutant leukemias have been traced to low-level TP53 clones detectable pre-HCT. These findings suggest that SCD itself may predispose patients to high-risk clonal hematopoiesis (CH). Prior studies of CH in SCD used sequencing methods with limited sensitivity, yielding conflicting conclusions and potentially missing small, clinically relevant clones. In this multinational cohort, we defined CH prevalence, age distribution, and mutational profiles in SCD relative to non-SCD controls and other hemoglobinopathies. Methods: We analyzed archived blood DNA from 7,283 individuals across 17 cohorts in 4 countries: 3,885 with SCD (SS, SC, Sꞵ0, Sꞵ+), 3,398 without SCD (AA, AS, AC), and 188 with beta-thalassemia. Using duplex sequencing, we identified somatic CH variants at ≥0.001 variant allele fraction (VAF), germline variants in leukemia predisposition genes, and HBB genotypes. CH was analyzed by gene and in pre-specified biological groups: DNMT3A/TET2 (DT-CH) and DNA damage response (DDR-CH: TP53, PPM1D, CHEK2, ATM). We used binomial logistic regression (age- and sex-adjusted) to compare t...