Mutation analysis links angioimmunoblastic T-cell lymphoma to clonal hematopoiesis and smoking

Abstract

Background:Although advance has been made in understanding the pathogenesis of mature T-cell neoplasms, the initiation and progression of angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), remain poorly understood. A subset of AITL/PTCL-NOS patients develop concomitant hematologic neoplasms (CHN), and a biomarker to predict this risk is lacking.Methods:We generated and analyzed the mutation profiles through 537-gene targeted sequencing of the primary tumors and matched bone marrow/peripheral blood samples in 25 patients with AITL and two with PTCL-NOS.Results:Clonal hematopoiesis (CH)-associated genomic alterations, found in 70.4% of the AITL/PTCL-NOS patients, were shared among CH and T-cell lymphoma, as well as concomitant myeloid neoplasms or diffuse large B-cell lymphoma (DLBCL) that developed before or after AITL. Aberrant AID/APOBEC activity-associated and tobacco smoking-associated mutational signatures were respectively enriched in the early CH-associated mutations and late non-CH-associated mutations during AITL/PTCL-NOS development. Moreover, analysis showed that the presence of CH harboring ≥2 pathogenic TET2 variants with ≥15% of allele burden conferred higher risk for CHN (p=0.0006, hazard ratio = 14.01, positive predictive value = 88.9%, negative predictive value = 92.1%).Conclusions:We provided genetic evidence that AITL/PTCL-NOS, CH, and CHN can frequently arise from common mutated hematopoietic precursor clones. Our data also suggests smoking exposure as a potential risk factor for AITL/PTCL-NOS progression. These findings provide insights into the cell origin and etiology of AITL and PTCL-NOS and provide a novel stratification biomarker for CHN risk in AITL patients.Funding:R01 grant (CA194547) from the National Cancer Institute to WT.

Pathologic and molecular insights in nodal T-follicular helper cell lymphomas

“…TET2 and DNMT3a mutations are the most frequent mutations in clonal hematopoiesis (CH). Many studies have now established that up to 80% of patients with TFH lymphomas carry the same TET2 and/or DNMT3A mutations identified in the Tcells and the myeloid cells (78)(79)(80). Furthermore, TET2 and DNMT3A mutations are not restricted to T-cells and myeloid cells but can also be identified in the admixed mature B-cells in the lymph nodes.…”

The emerging role of TET enzymes in the immune microenvironment at the maternal-fetal interface during decidualization and early pregnancy

“…Strikingly, TET loss of function is strongly associated with hematological malignancies. For example, TET2 loss-of-function mutations are frequently observed in myelodysplastic syndromes and myeloid malignancies as well as in certain peripheral T-cell lymphomas ( 54 – 57 ). The biological roles of TET proteins in immune cell development, function, and malignant transformation have been unraveled in these studies.…”

Clonal Hematopoiesis and the Heart: a Toxic Relationship

“…Murine Tet2 knockouts demonstrate that loss or heterozygosity of Tet2 leads to myeloid progenitor cell and multipotent progenitor cell expansion, and that hematopoietic stem cells harboring Tet2 loss can outcompete wildtype hematopoietic stem cells in competitive engraftment experiments [40][41][42][43][44]. TET2 mutations are frequently found in myeloid neoplasms but also in angioimmunoblastic T-cell lymphoma and in peripheral T-cell lymphoma not otherwise specified [39,[45][46][47][48].…”