Clonal hematopoiesis in adult pure red cell aplasia

Naohito Fujishima,Shinya Sato,Yasushi Miyazaki,Ayumi Omokawa,Yasuhito Nannya,Shigeharu Ueki,Kenichi Sawada,Kaoru Tohyama,Hiroshi Yamasaki,Shinji Nakao,Souichi Koyota,Fumihiro Ishida,Tomoo Saga,Yasuhiro Nakashima,Kensuke Usuki,Kinuko Mitani,Keiji Kuba,Junki Kohmaru,Yuki Moritoki,Akio Ohta ,Seishi Ogawa,Akihisa Matsuda ,Makoto Hirokawa

doi:10.1038/s41598-021-81890-5

Abstract

Idiopathic pure red cell aplasia (PRCA) and secondary PRCA associated with thymoma and large granular lymphocyte leukemia are generally considered to be immune-mediated. The PRCA2004/2006 study showed that poor responses to immunosuppression and anemia relapse were associated with death. PRCA may represent the prodrome to MDS. Thus, clonal hematopoiesis may be responsible for treatment failure. We investigated gene mutations in myeloid neoplasm-associated genes in acquired PRCA. We identified 21 mutations affecting amino acid sequences in 11 of the 38 adult PRCA patients (28.9%) using stringent filtering of the error-prone sequences and SNPs. Four PRCA patients showed 7 driver mutations in TET2, DNMT3A and KDM6A, and 2 PRCA patients carried multiple mutations in TET2. Five PRCA patients had mutations with high VAFs exceeding 0.3. These results suggest that clonal hematopoiesis by stem/progenitor cells might be related to the pathophysiology of chronic PRCA in certain adult patients.

Highlights

Idiopathic pure red cell aplasia (PRCA) and secondary PRCA associated with thymoma and large granular lymphocyte leukemia are generally considered to be immune-mediated
To test the working hypothesis that clonal hematopoiesis by stem/progenitor cells might be related to the poor responses and outcomes of PRCA patients, we investigated how often clonal hematopoiesis is detected in adult chronic PRCA
We identified at least one genomic mutation in 11 out of 38 patients with PRCA (28.9%), and we observed one mutation in only 1 out of 13 patients with aplastic anemia (p = 0.151, Fisher test) and at least one mutation in 7 out of 9 patients with myeloid neoplasms (p = 0.0178, Fisher test) (Fig. 1)

Summary

Introduction

Idiopathic pure red cell aplasia (PRCA) and secondary PRCA associated with thymoma and large granular lymphocyte leukemia are generally considered to be immune-mediated. Five PRCA patients had mutations with high VAFs exceeding 0.3 These results suggest that clonal hematopoiesis by stem/progenitor cells might be related to the pathophysiology of chronic PRCA in certain adult patients. There are two potential mechanisms of unresponsiveness to immunosuppression: clonal changes in autoaggressive lymphocytes reacting against erythroid progenitors and clonal hematopoiesis by stem/progenitor cells that have undergone somatic mutations during the disease progression of PRCA Regarding the former, mutations in the signal transducer and activator of the transcription 3 gene (STAT3) were detected in 40% of patients with large granular lymphocyte (LGL) leukemia[12] and have been found in PRCA13, aplastic anemia, and MDS p atients[14]. Patients, including LGL leukemia-associated PRCA, idiopathic PRCA and thymoma-associated PRCA15 They reported that STAT3 mutation-positive patients were less responsive to cyclosporine than those with wildtype STAT3.

Methods

Results

Conclusion