[Genetic abnormalities in bone marrow failure].

Kohei Hosokawa
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Abstract

Bone marrow (BM) failure is a condition characterized by peripheral pancytopenia resulting from decreased hematopoiesis in the BM. It includes congenital disorders such as Fanconi anemia (FA), as well as acquired conditions such as acquired aplastic anemia (AA), myelodysplastic syndrome (MDS), and paroxysmal nocturnal hemoglobinuria (PNH). AA presents with pancytopenia and BM hypoplasia, primarily triggered by an autoimmune mechanism involving T cells that damage hematopoietic stem cells (HSCs). Genomic investigations utilizing next-generation sequencing or SNP arrays have revealed that clonal hematopoiesis by HSCs with genetic aberrations, including PIGA, DNMT3A, ASXL1, BCOR/BCORL1, copy-number neutral LOH of chromosome 6p (6pLOH), and somatic mutations in HLA class I alleles are prevalent in AA patients. Recent studies have identified somatic mutations in genes associated with the JAK-STAT and MAPK pathways in T cells of AA patients. Genomic abnormalities in AA differ from those observed in MDS and age-related clonal hematopoiesis. Notably, the presence of PNH-type cells and HLA class I allele-lacking cells represent two major instances of escape hematopoiesis, which indicate the presence of HSCs evading autoimmune T cell attacks. These findings provide crucial insights into the immune pathophysiology of BM failure.

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[骨髓衰竭的遗传异常]。
骨髓(BM)衰竭是一种因骨髓造血功能减退而导致的外周泛发性贫血。它包括范可尼贫血(FA)等先天性疾病,以及获得性再生障碍性贫血(AA)、骨髓增生异常综合征(MDS)和阵发性夜间血红蛋白尿(PNH)等后天性疾病。再生障碍性贫血表现为全血细胞减少和BM发育不良,主要由T细胞损伤造血干细胞(HSCs)的自身免疫机制引发。利用下一代测序或SNP阵列进行的基因组学调查显示,AA患者中普遍存在造血干细胞克隆性造血,并伴有基因畸变,包括PIGA、DNMT3A、ASXL1、BCOR/BCORL1、染色体6p的拷贝数中性LOH(6pLOH)以及HLA I类等位基因的体细胞突变。最近的研究发现,在 AA 患者的 T 细胞中,与 JAK-STAT 和 MAPK 通路相关的基因发生了体细胞突变。AA 基因组异常与在 MDS 和年龄相关克隆性造血中观察到的异常不同。值得注意的是,PNH 型细胞和缺乏 HLA I 类等位基因细胞的存在代表了逃避性造血的两大实例,这表明存在逃避自身免疫 T 细胞攻击的造血干细胞。这些研究结果为了解造血干细胞衰竭的免疫病理生理学提供了重要的启示。
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