TET2 and clonal hematopoiesis-related gene variants in patients with acquired pure red cell aplasia

Abstract

Abstract Dysregulation of T cell-mediated immunity is considered a major pathophysiological mechanism of acquired pure red cell aplasia (PRCA), such as idiopathic PRCA, large granular lymphocytic leukemia-associated PRCA, and thymoma-associated PRCA. Although STAT3 mutations are frequently detected in PRCA patients, other mutational profiles and their involvement in the clinical characteristics are yet to be clarified. Whole-exome sequencing and targeted sequencing were performed using a custom-designed panel for PRCA (n = 53). The frequently mutated genes were NEB (40%), STAT3 (36%), PCLO (30%), TET2 (23%), and KMT2D (15%). Four of the 12 patients with mutations in TET2 had germline TET2 variants. Patients positive for TET2 variants had significantly more variants of lymphoid clonal hematopoiesis-related genes than those without TET2 variants (11/12 vs. 23/41, P = 0.038). Patients with TET2 variants relapsed after immunosuppressive therapy more frequently than those without TET2 variant (55% [6/11] vs. 11% [4/35], P = 0.0065). These data suggest that variants of clonal hematopoiesis-related genes, including TET2, in addition to STAT3, play important roles in the pathophysiology of PRCA.