Clonal hematopoiesis and lymphoma-associated mutations in hematopoietic progenitors in B-cell non-Hodgkin lymphoma
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.
Article Details
Authors (23)
Laura Wiegand
1Department of Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany
Patricia Silva
Daniel Noerenberg
1Department of Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany
Friederike Christen
1Department of Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany
Klara Kopp
1Department of Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany
Benjamin Nick Locher
1Department of Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany
Pelle Löwe
1Department of Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany
Marlon Tilgner
1Department of Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany
Robert Altwasser
Vanessa Storzer
1Department of Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany
Catarina Marlene Stein
1Department of Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany
Franziska Briest
1Department of Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany
Christopher Maximilian Arends
1Department of Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany
Mareike Frick
Charité–Universitätsmedizin Berlin, Berlin
Jana Ihlow
2Institute of Pathology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
Anna Dolnik
1Department of Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany
Naveed Ishaque
Ulrich Keller
Il-Kang Na
Livius Penter
Lars Bullinger
Raphael Hablesreiter
1Department of Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany
Frederik Damm
Charité–Universitätsmedizin Berlin, Berlin