Genetic links in angioimmunoblastic T-cell lymphoma (AITL), clonal hematopoiesis and concomitant hematologic malignancies provide insights into the cell of origin, etiology and biomarker discovery for AITL

We generated and compared the mutation profiles through targeted sequencing of the primary tumors and matched bone marrow/peripheral blood samples in 25 patients with angioimmunoblastic T-cell lymphoma (AITL) and 2 with peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). Our results provided strong evidence that AITL/PTCL-NOS, clonal hematopoiesis (CH) as well as other concomitant myeloid and even B-cell hematologic neoplasms (CHN), frequently arose from common mutated hematopoietic stem cell clones. Aberrant AID/APOBEC activity-associated substitutions and tobacco smoking-associated substitutions were enriched in the early CH-associated mutations and late non-CH associated mutations during AITL/PTCL-NOS development, respectively. Moreover, survival analysis showed that the presence of CH harboring ≥ 2 pathogenic TET2 variants with ≥ 15% of allele burden conferred higher risk for CHN (P = 0.0034, hazard ratio = 10.81). These findings provide insights into the cell origin and etiology of AITL, and provide a novel stratification biomarker for CHN risk in AITL/PTCL-NOS patients.