![]() ![]() To address this issue, we investigated the expression of the HLA alleles in the HSPCs of AA patients whose granulocytes are completely replaced with HLA(−) cells. As HLA(−) HSPCs often produce clonal hematopoiesis with their HLA(−) progenies, studying HLA(−) HSPCs may be useful for clarifying the phenotype unique to healthy HSPCs, which substantially contribute to hematopoiesis and could be different from the phenotype of HSPCs with myeloid malignancy‐related gene mutations. HLA(−) HSPCs are thought to be healthy HSPCs that escape T‐cell attack due to the lack of particular HLA‐class I alleles that present autoantigens of HSPCs to T cells in AA. Rare exceptions include HLA class I allele‐lacking (HLA) HSPCs, which are detected in approximately 30% of AA patients. Different from murine HSPCs that can be marked by transduced genes, it is generally impossible to know which HSPCs do or do not contribute to hematopoiesis due to a lack of useful markers on healthy HSPCs, which are responsible for active hematopoiesis. Hematopoiesis in humans is thought to be supported by a limited number of HSPCs selected from a large number of HSPCs that remain dormant in the BM. Phenotypic changes in the HSPCs associated with somatic mutations are unknown either. The prognostic significance of such somatic mutations therefore remains unclear. Some of these somatic mutations indeed predispose secondary myelodysplastic syndromes (MDS), whereas others do not directly contribute to the development of secondary MDS. However, recent studies using next‐generation sequencing have revealed that approximately one third of newly diagnosed AA patients have clonal hematopoiesis by HSPCs with somatic mutations of myeloid malignancy‐related genes. As the main pathophysiology of AA is a reduction of hematopoietic stem progenitor cells (HSPCs) due to T‐cell attacks against HSPCs, HSPCs themselves are thought to be healthy and give rise to polyclonal hematopoiesis. The increased expression of CXCR4 may therefore reflect intrinsic abnormalities of HSPCs caused by somatic mutations that allow them to evade restriction by BM stromal cells.Īcquired aplastic anemia (AA) is a syndrome characterized by pancytopenia and bone marrow (BM) hypoplasia without apparent dysplasia in the BM cells and an increase in the number of blasts. In contrast, the median percentage was much higher (78% ) in the five AA patients without HLA(−) granulocytes possessing somatic mutations ( c‐kit, t, monosomy 7, ASXL1 ), findings that were comparable to those (66.5%, 63.1%–88.9%) in the four patients with advanced myelodysplastic syndromes. In comparison to healthy individuals ( n = 15, 12.3%–49.9%, median 43.2%), the median CXCR4 + cell percentages in the HSPCs of patients without somatic mutations were low: 29.3% (14.3%–37.3%) in the eight patients without HLA(−) granulocytes, 8.8% (4.1%–9.8%) in the five patients with HLA(−) cells accounting for >90% of granulocytes, and 7.8 (2.1%–8.7%) in the six patients with paroxysmal nocturnal hemoglobinuria. As our initial study showed increased CXCR4 expression on HLA allele‐lacking (HLA) HSPCs that solely support hematopoiesis in comparison to redundant HLA(+) HSPCs in AA patients, we screened the HSPCs of patients with various types of bone marrow (BM) failure to investigate their CXCR4 expression. The phenotypic changes in hematopoietic stem progenitor cells (HSPCs) with somatic mutations of malignancy‐related genes in patients with acquired aplastic anemia (AA) are poorly understood. ![]()
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