Tracing Clonal Hematopoiesis and Lymphoma-Associated Mutations in Hematopoietic Progenitors in B-Cell Non-Hodgkin Lymphoma (B-NHL)

Unlike in leukemia and solid tumors, the role of disease-initiating precursors in B-cell non-Hodgkin lymphomas (B-NHLs) remains underexplored. Such precursors may drive clonal evolution, contributing to the chronic nature of indolent NHLs. Here, we systematically profiled genetic precursor lesions and clonal dynamics using complementary sequencing approaches in a cohort of 43 B-NHLs. Targeted sequencing identified clonal hematopoiesis-associated mutations in the peripheral blood of 55% of patients. Deep sequencing of flow-sorted populations revealed B-cell-skewed propagation, contrasting with findings in individuals without hematologic malignancies. Several mutated clones showed clonal expansion in corresponding tumors, particularly those harboring TP53, EZH2 and TET2 mutations, but not DNMT3A mutant clones. Moreover, we detected lymphoma-associated mutations in hematopoietic progenitor cells (HPCs) in indolent but not aggressive NHLs. Using single-cell genotyping, we provide evidence of mutated HPCs in three follicular lymphoma (FL) cases. Our findings support a pre-neoplastic state in FL pathogenesis, underscoring the potential for novel therapeutic approaches targeting disease-initiating precursors.