LAUSR

Clonal hematopoiesis predisposes to hematologic malignancies. However, clonal hematopoiesis is understudied in classic Hodgkin lymphoma (cHL), a mature B-cell neoplasm exhibiting the most abundant microenvironment. We analyzed clonal hematopoiesis in 40 cHL cases by sequencing microdissected tumor cells and matched normal cells from blood and/or lymph nodes. Five patients had blood and/or tissue clonal hematopoiesis. In three of five patients (all failing first-line therapy), clonal hematopoiesis spread through the tissue microenvironment extensively, and featured mutant DNMT3A R882H, KRAS G60D, and DNMT3A R882H+TET2 Q1274* in 33%, 92%, and 60% of nonneoplastic cells, respectively. In the latter case, DNMT3A/TET2-mutant clonal hematopoiesis seeded the neoplastic clone, which was infected by the Epstein-Barr virus and showed almost no other somatic mutations exome-wide. In the former case, DNMT3A-mutant clonal hematopoiesis did not originate the neoplastic clone despite dominating the blood and B-cell lineage (∼94% leukocytes; ∼96% mature blood B cells), yet led to NPM1-mutated acute myeloid leukemia 6 years after therapy for cHL. Our results expand to cHL the spectrum of hematologic malignancies associated with clonal hematopoiesis. SIGNIFICANCE: Clonal hematopoiesis can be present in the cHL tissue, can give rise to the tumor clone, and can spread to large parts of its microenvironment. Even when massive, clonal hematopoiesis does not always give rise to the neoplastic clone of multiple myeloid and lymphoid neoplasms occurring in the same patient.