Clonal hematopoiesis and lymphoma-associated mutations in hematopoietic progenitors in B-cell non-Hodgkin lymphoma
Laura Wiegand, PATRÍCIA ROCHA SILVA, Daniel Noerenberg, Friederike Christen, Klara Kopp, Benjamin N. Locher, Pelle Löwe, Marlon Tilgner, Robert Altwasser, Vanessa Storzer, Catarina M. Stein, Franziska Briest, Christopher Maximilian Arends, Mareike Frick, Jana Ihlow, Anna Dolnik, Naveed Ishaque, Ulrich Keller, Il‐Kang Na, Livius Penter, Lars Bullinger, Raphael Hablesreiter, Frédérik Damm
Abstract
ABSTRACT: The contribution of clonal hematopoiesis (CH) and disease-initiating precursors in B-cell non-Hodgkin lymphomas (B-NHLs) remains underexplored. Such precursors may drive clonal evolution, contributing to disease progression and relapse. Here, we systematically profiled genetic precursor lesions in 43 patients with B-NHL using complementary whole-exome, targeted, and single-cell sequencing approaches. CH-associated mutations with a variant allele frequency of ≥1% were detected in the peripheral blood of 55% of patients, with significantly higher frequencies in indolent compared with aggressive B-NHL (P = .03). Quantification of allele burden in flow-sorted cell populations revealed a B-cell-skewed expansion of CH clones, contrasting the myeloid differentiation bias reported in individuals without hematologic malignancies. Gene-specific expansion patterns were evident among the most frequent CH lesions, with DNMT3A-mutant clones exhibiting impaired hematopoietic differentiation and TET2-mutant clones having multilineage propagation. Notably, identical CH clones were detected in 41% of corresponding lymphomas, displaying distinct clonal dynamics: tumor-promoting CH (expansion in B-NHL; 10/16 clones; mainly TP53) and tumor-infiltrating CH (no expansion; mainly DNMT3A). Moreover, we identified lymphoma-associated mutations in flow-sorted hematopoietic progenitors from patients with indolent but not aggressive B-NHL and observed a stepwise accumulation of mutations along the lymphoid differentiation path. Single-cell genotyping confirmed the presence of mutated progenitors in 3 follicular, 2 mantle cell, and 2 marginal zone lymphoma patients, providing direct evidence of a preneoplastic state in disease pathogenesis. Our findings offer novel insight into the cellular origin of nodal B-NHLs and highlight a previously underappreciated role for early clonal events involving the stem/progenitor cell compartment.