Sustained clonal hematopoiesis by HLA-lacking hematopoietic stem cells without driver mutations in aplastic anemia.

Autor:	Imi T; Department of Hematology and., Katagiri T; Department of Clinical Laboratory Sciences, Graduate School of Medical Sciences, and., Hosomichi K; Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan; and., Zaimoku Y; Department of Hematology and., Hoang Nguyen V; Department of Hematology and., Nakagawa N; Department of Hematology and., Tajima A; Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan; and., Yoshizato T; Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Ogawa S; Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan., Nakao S; Department of Hematology and.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2018 May 08; Vol. 2 (9), pp. 1000-1012.
DOI:	10.1182/bloodadvances.2017013953
Abstrakt:	Clonal hematopoiesis by hematopoietic stem progenitor cells (HSPCs) that lack an HLA class I allele (HLA - HSPCs) is common in patients with acquired aplastic anemia (AA); however, it remains unknown whether the cytotoxic T lymphocyte (CTL) attack that allows for survival of HLA - HSPCs is directed at nonmutated HSPCs or HSPCs with somatic mutations or how escaped HLA - HSPC clones support sustained hematopoiesis. We investigated the presence of somatic mutations in HLA - granulocytes obtained from 15 AA patients in long-term remission (median, 13 years; range, 2-30 years). Targeted sequencing of HLA - granulocytes revealed somatic mutations ( DNMT3A , n = 2; TET2 , ZRSR2 , and CBL , n = 1) in 3 elderly patients between 79 and 92 years of age, but not in 12 other patients aged 27 to 74 years (median, 51.5 years). The chronological and clonogenic analyses of the 3 cases revealed that ZRSR2 mutation in 1 case, which occurred in an HLA - HSPC with a DNMT3A mutation, was the only mutation associated with expansion of the HSPC clone. Whole-exome sequencing of the sorted HLA - granulocytes confirmed the absence of any driver mutations in 5 patients who had a particularly large loss of heterozygosity in chromosome 6p (6pLOH) clone size. Flow-fluorescence in situ hybridization analyses of sorted HLA + and HLA - granulocytes showed no telomere attrition in HLA - granulocytes. The findings suggest that HLA - HSPC clones that escape CTL attack are essentially free from somatic mutations related to myeloid malignancies and are able to support long-term clonal hematopoiesis without developing driver mutations in AA patients unless HLA loss occurs in HSPCs with somatic mutations. (© 2018 by The American Society of Hematology.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu