biostudies-literatureSaygin CCancer Research FoundationNHLBI NIH HHSNCI NIH HHSNational Institutes of HealthElsa U. Pardee FoundationPrevent Cancer FoundationLeukemia and Lymphoma Society164-179https://www.ebi.ac.uk/biostudies/studies/S-EPMC11061587biostudies-literatureUnknown5(3)Myeloid neoplasms arise from preexisting clonal hematopoiesis (CH); however, the role of CH in the pathogenesis of acute lymphoblastic leukemia (ALL) is unknown. We found that 18% of adult ALL cases harbored TP53, and 16% had myeloid CH-associated gene mutations. ALL with myeloid mutations (MyM) had distinct genetic and clinical characteristics, associated with inferior survival. By using single-cell proteogenomic analysis, we demonstrated that myeloid mutations were present years before the diagnosis of ALL, and a subset of these clones expanded over time to manifest as dominant clones in ALL. Single-cell RNA sequencing revealed upregulation of genes associated with cell survival and resistance to apoptosis in B-ALL with MyM, which responds better to newer immunotherapeutic approaches. ThBlood cancer discoveryAcute Lymphoblastic Leukemia with Myeloid Mutations Is a High-Risk Disease Associated with Clonal Hematopoiesis.PMC11061587P01CA066996P50CA206963P50 CA206963P01 CA066996R01HL082945R01 HL082945F30 HL162455K08 CA252174Steidl UEbert BLWanjari PArber DAZhang PUmesh Nagalakshmi SLarson RAGodley LAStock WSaygin CLager AMOdenike OMGibson CJWang PStauber JWeeks LDMunshi NCCheng JXAldoss IPatel AAMarcucci GKnepper TCSegal JPEisfelder BJShah BDLuskin MRLapalombella RSperling ASGreally JMVenkataraman GGharghabi MJayaram SFitzpatrick CGurbuxani SBohorquez OfalseAcute Lymphoblastic Leukemia with Myeloid Mutations Is a High-Risk Disease Associated with Clonal Hematopoiesis.Myeloid neoplasms arise from preexisting clonal hematopoiesis (CH); however, the role of CH in the pathogenesis of acute lymphoblastic leukemia (ALL) is unknown. We found that 18% of adult ALL cases harbored TP53, and 16% had myeloid CH-associated gene mutations. ALL with myeloid mutations (MyM) had distinct genetic and clinical characteristics, associated with inferior survival. By using single-cell proteogenomic analysis, we demonstrated that myeloid mutations were present years before the diagnosis of ALL, and a subset of these clones expanded over time to manifest as dominant clones in ALL. Single-cell RNA sequencing revealed upregulation of genes associated with cell survival and resistance to apoptosis in B-ALL with MyM, which responds better to newer immunotherapeutic approaches. Th2024-01-01T00:00:00Z2024 May2026-06-02T18:38:01.404Z2025-04-04T00:29:35.064ZS-EPMC110615873815018410.1158/2643-3230.BCD-23-0106