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| Item Type: | Article |
|---|---|
| Title: | Clonal hematopoiesis and lymphoma-associated mutations in hematopoietic progenitors in B-cell non-Hodgkin lymphoma |
| Creators Name: | Wiegand, Laura, Silva, Patricia, Noerenberg, Daniel, Christen, Friederike, Kopp, Klara, Locher, Benjamin Nick, Löwe, Pelle, Tilgner, Marlon, Altwasser, Robert, Storzer, Vanessa, Stein, Catarina Marlene, Briest, Franziska, Arends, Christopher Maximilian, Frick, Mareike, Ihlow, Jana, Dolnik, Anna, Ishaque, Naveed, Keller, Ulrich, Na, Il-Kang, Penter, Livius, Bullinger, Lars, Hablesreiter, Raphael and Damm, Frederik |
| 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. |
| Keywords: | B-Cell Lymphoma, Clonal Evolution, Clonal Hematopoiesis, DNA Methyltransferase 3A, Hematopoietic Stem Cells, Mutation |
| Source: | Blood |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Volume: | 147 |
| Number: | 15 |
| Page Range: | 1723-1734 |
| Date: | 9 April 2026 |
| Official Publication: | https://doi.org/10.1182/blood.2025030489 |
| PubMed: | View item in PubMed |
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