RESUMEN
Normal hematopoietic stem and progenitor cells (HSPCs) inherently accumulate somatic mutations and lose clonal diversity with age, processes implicated in the development of myeloid malignancies 1 . The impact of exogenous stressors, such as cancer chemotherapies, on the genomic integrity and clonal dynamics of normal HSPCs is not well defined. We conducted whole-genome sequencing on 1,032 single-cell-derived HSPC colonies from 10 patients with multiple myeloma (MM), who had undergone various chemotherapy regimens. Our findings reveal that melphalan treatment distinctly increases mutational burden with a unique mutation signature, whereas other MM chemotherapies do not significantly affect the normal mutation rate of HSPCs. Among these therapy-induced mutations were several oncogenic drivers such as TET2 and PPM1D . Phylogenetic analysis showed a clonal architecture in post-treatment HSPCs characterized by extensive convergent evolution of mutations in genes such as TP53 and PPM1D . Consequently, the clonal diversity and structure of post-treatment HSPCs mirror those observed in normal elderly individuals, suggesting an accelerated clonal aging due to chemotherapy. Furthermore, analysis of matched therapy-related myeloid neoplasm (t-MN) samples, which occurred 1-8 years later, enabled us to trace the clonal origin of t-MNs to a single HSPC clone among a group of clones with competing malignant potential, indicating the critical role of secondary mutations in dictating clonal dominance and malignant transformation. Our findings suggest that cancer chemotherapy promotes an oligoclonal architecture with multiple HSPC clones possessing competing leukemic potentials, setting the stage for the selective emergence of a singular clone that evolves into t-MNs after acquiring secondary mutations. These results underscore the importance of further systematic research to elucidate the long-term hematological consequences of cancer chemotherapy.
RESUMEN
Lymphoplasmacytic lymphoma (LPL) with IgG or IgA paraprotein is rare and a subset of cases can mimic a plasma cell neoplasm (PCN). We studied 29 such cases to explore their clinicopathological features and the best diagnostic approaches with a focus on bone marrow findings. The cohort included 18 men and 11 women with a median age of 68 years. The median M protein was 3.1 g/dL, IgG in 19 patients (66%), IgA in 9 (31%), and dual IgG/IgA in 1 (3%). All patients had bone marrow involvement with CD138+ plasma cells (PCs) ranging from 1 to 35% (median, 10%). Two patients also had amyloidosis. Immunoglobulin light chain concordant monotypic PCs and monotypic B cells were identified in 96% of cases assessed by flow cytometry. Notably, the neoplastic PCs were consistently positive for CD45 (dim, 100%), CD19 (96%), CD81 (89%), CD27 (83%), rarely and only weakly or partially express CD56 (16%), whereas CD117 was consistently negative. Eleven cases analyzed by fluorescence in situ hybridization were negative for CCND1::IGH and myeloma-related aberrations. MYD88 mutation was detected in 17 of 24 cases (71%), and CXCR4 mutation was identified in 6 of 19 cases (32%), of which 4 had concurrent MYD88 mutation. In conclusion, the results highlight a potential diagnostic pitfall of LPL associated with marked plasmacytic differentiation and an IgG or IgA paraprotein that can resemble a PCN. Useful features in favor of LPL against PCN include the characteristic immunophenotypic profile of the PCs in LPL, absence of CCND1::IGH, and the presence of MYD88 and/or CXCR4 mutations.
