Gene-specific expansion patterns were evident among the most frequent CH lesions, with DNMT3A-mutant clones exhibiting impaired hematopoietic differentiation and TET2-mutant clones showing multi-lineage 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 pre-neoplastic 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.
Wiegand et al. (Mon,) studied this question.