Journal Article

DKFZ-2026-00840

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Clonal hematopoiesis and lymphoma-associated mutations in hematopoietic progenitors in B-cell non-Hodgkin lymphoma.

Wiegand, L. ; Silva, P. ; Noerenberg, D. ; Christen, F. ; Kopp, K. ; Locher, B. N. ; Löwe, P. ; Tilgner, M. ; Altwasser, R. ; Storzer, V. ; Stein, C. M. ; Briest, F. ; Arends, C. M. ; Frick, M. ; Ihlow, J. ; Dolnik, A. ; Ishaque, N. ; Keller, U.DKFZ* ; Na, I.-K. ; Penter, L.DKFZ* ; Bullinger, L.DKFZ* ; Hablesreiter, R.DKFZ* ; Damm, F.DKFZ*

2026
American Society of Hematology Washington, DC

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.

Keyword(s): Humans (MeSH) ; Clonal Hematopoiesis: genetics (MeSH) ; Mutation (MeSH) ; Hematopoietic Stem Cells: pathology (MeSH) ; Hematopoietic Stem Cells: metabolism (MeSH) ; Lymphoma, B-Cell: genetics (MeSH) ; Lymphoma, B-Cell: pathology (MeSH) ; Female (MeSH) ; Middle Aged (MeSH) ; Male (MeSH) ; Aged (MeSH) ; Adult (MeSH) ; Aged, 80 and over (MeSH) ; Clonal Evolution (MeSH) ; DNA Methyltransferase 3A (MeSH) ; DNA Methyltransferase 3A

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Berlin (BE01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2026

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 20 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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