Hematopoietic stem progenitor cells lacking HLA differ from those lacking GPI-anchored proteins in the hierarchical stage and sensitivity to immune attack in patients with acquired aplastic anemia

Yoroidaka, Takeshi; Hosokawa, Kohei; Imi, Tatsuya; Mizumaki, Hiroki; Katagiri, Takamasa; Ishiyama, Ken; Yamazaki, Hirohito; Azuma, Fumihiro; Nanya, Yasuhito; Ogawa, Seishi; Nakao, Shinji

doi:10.1038/s41375-021-01202-8

Cited by 6 publications

(5 citation statements)

References 37 publications

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“…This discrepancy in the percentage of affected cells between CD34 + cells and granulocytes was not seen in GPI(−) cells (data not shown). We recently demonstrated that HLA(−) HSPCs differed from GPI(−) HSPCs in hierarchy and in the sensitivity to immune attack in patients with AA, and the immune attack against HPCS persisted subclinically, even in patients who were in complete remission, allowing for the expansion of HLA(−) HSPCs [ 22 ]. The persistent immune pressure by cytotoxic T lymphocytes (CTLs) may eliminate the progeny of HLA(+) CMPs, leading to the predominance of HLA(−) cells in more committed progenitor cells than CMPs.…”

Section: Discussionmentioning

confidence: 99%

Hematopoietic stem progenitor cells with malignancy‐related gene mutations in patients with acquired aplastic anemia are characterized by the increased expression of CXCR4

Katagiri

Espinoza

Uemori

et al. 2022

eJHaem

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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. 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.

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Section: Discussionmentioning

confidence: 99%

Hematopoietic stem progenitor cells with malignancy‐related gene mutations in patients with acquired aplastic anemia are characterized by the increased expression of CXCR4

Katagiri

Espinoza

Uemori

et al. 2022

eJHaem

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“…The reason for the moderate increase in WT1 gene expression in granulocytes from AA patients during convalescence after treatment remains obscure. Our recent study showed that immune attack on HSC persists even in AA patients who achieve complete response after successful IST and favors the proliferation of human leukocyte antigens class I allele-lacking HSCs [27]. Inflammatory cytokines secreted during persistent immune attack may prevent HSCs from undergoing effective maturation, which eventually leads to increased WT1 gene expression in their progeny.…”

Section: Discussionmentioning

confidence: 99%

Clinical significance of the increased expression of the WT1 gene in peripheral blood of patients with acquired aplastic anemia

Ishiyama

Dung

Imi

et al. 2022

eJHaem

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To determine the significance of increased Wilms tumor 1 (WT1) gene expression in the peripheral blood of patients with acquired aplastic anemia (AA), we analyzed serial changes in WT1 mRNA copy number (WT1cn) in 63 patients with AA as well as in five patients with myelodysplastic syndromes (MDS) and seven patients with paroxysmal nocturnal hemoglobinuria (PNH). WT1cn was higher than the cut‐off (≥50 copies/μg RNA) at the time of the first measurement in 41% of untreated (60–190 copies/μg RNA [median 130]) and 59% of treated (59–520 copies/μg RNA [median 150]) AA patients. Although WT1cns gradually increased in most AA patients during the 2–105 months follow‐up period, they did not lead to clonal evolution except in three patients in whom the maximum change ratio of WT1cn (WT1cn‐change max), defined as the ratio of WT1cn at the first examination to that of the maximum value, exceeded 20.0 and who developed MDS at 2, 46, and 105 months. Increased WT1 gene expression was enriched in granulocytes rather than in mononuclear cells in most WT1‐positive AA patients and did not correlate with mutations of genes associated with myeloid malignancy. WT1cns were high at 690–5700 (median 2000) in MDS patients and remained high thereafter, while WT1cns in PNH patients (77–200; median 96) were similar to those in AA. Thus, moderate increases in WT1cns up to 600 are common in AA patients in stable remission. An increase in the WT1cn‐change max over 20.0 may portend transformation from AA to MDS.

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“…PIGA muta tions occur early in hema to poi e sis in hema to poietic stem cells or multipotent pro gen i tors. 7,12,14,15 In most patients, PNH clones can be detected in all or most mature hema to poietic lin e ages, includ ing granulocytes, mono cytes, plate lets, RBCs, and the B, T, and nat u ral killer cells. 7,12,15 More lim ited lin eage involve ment can occur but is more char ac ter is tic of MDS, in which PNH clones are also more likely to be tran sient.…”

Section: Clinical Case 1: False-positive Pnh Testmentioning

confidence: 99%

“…7,12,14,15 In most patients, PNH clones can be detected in all or most mature hema to poietic lin e ages, includ ing granulocytes, mono cytes, plate lets, RBCs, and the B, T, and nat u ral killer cells. 7,12,15 More lim ited lin eage involve ment can occur but is more char ac ter is tic of MDS, in which PNH clones are also more likely to be tran sient. 7 Next-gen er a tion sequenc ing of the PIGA gene in patients with PNH iden ti fied 2 or more inde pen dent PIGA muta tions in 85% of patients with PNH and at least 3 inde pen dent PIGA muta tions in 57% of patients.…”

Section: Clinical Case 1: False-positive Pnh Testmentioning

confidence: 99%

When does a PNH clone have clinical significance?

Babushok

2021

Hematology

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Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired blood disease caused by somatic mutations in the phosphatidylinositol glycan class A (PIGA) gene required to produce glycophosphatidyl inositol (GPI) anchors. Although PNH cells are readily identified by flow cytometry due to their deficiency of GPI-anchored proteins, the assessment of the clinical significance of a PNH clone is more nuanced. The interpretation of results requires an understanding of PNH pathogenesis and its relationship to immune-mediated bone marrow failure. Only about one-third of patients with PNH clones have classical PNH disease with overt hemolysis, its associated symptoms, and the highly prothrombotic state characteristic of PNH. Patients with classical PNH benefit the most from complement inhibitors. In contrast, two-thirds of PNH clones occur in patients whose clinical presentation is that of bone marrow failure with few, if any, PNH-related symptoms. The clinical presentations are closely associated with PNH clone size. Although exceptions occur, bone marrow failure patients usually have smaller, subclinical PNH clones. This review addresses the common scenarios that arise in evaluating the clinical significance of PNH clones and provides practical guidelines for approaching a patient with a positive PNH result.

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Hematopoietic stem progenitor cells lacking HLA differ from those lacking GPI-anchored proteins in the hierarchical stage and sensitivity to immune attack in patients with acquired aplastic anemia

Cited by 6 publications

References 37 publications

Hematopoietic stem progenitor cells with malignancy‐related gene mutations in patients with acquired aplastic anemia are characterized by the increased expression of CXCR4

Hematopoietic stem progenitor cells with malignancy‐related gene mutations in patients with acquired aplastic anemia are characterized by the increased expression of CXCR4

Clinical significance of the increased expression of the WT1 gene in peripheral blood of patients with acquired aplastic anemia

When does a PNH clone have clinical significance?

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