Individual Hematopoietic Stem Cells in Human Bone Marrow of Patients with Aplastic Anemia or Myelodysplastic Syndrome Stably Give Rise to Limited Cell Lineages

Abstract

Mutation of the phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIG-A) gene in hematopoietic stem cells (HSCs) results in the loss of glycosylphosphatidylinositol-anchored proteins (GPI-APs) on HSCs, but minimally affects their development, and thus can be used as a clonal maker of HSCs. We analyzed GPI-APs expression on six major lineage cells in a total of 574 patients with bone marrow (BM) failure in which microenvironment itself is thought to be unaffected, including aplastic anemia (AA) or myelodysplastic syndrome (MDS). GPI-APs-deficient (GPIAPs 2 ) cells were detected in 250 patients. Whereas the GPIAPs 2 cells were seen in all six lineages in a majority of patients who had higher proportion ([dbmtequ]3%) of GPIAPs 2 cells, they were detected in only limited lineages in 92.9% of cases in the lower proportion (<3%) group. In all 250 cases, the same lineages of GPI-APs 2 cells were detected even after 6-18-month intervals, indicating that the GPIAPs 2 cells reflect hematopoiesis maintained by a self-renewing HSC in most of cases. The frequency of clones with limited lineages seen in mild cases of AA was similar to that in severe cases, and clones with limited lineages were seen even in two health volunteer cases. These results strongly suggest most individual HSCs produce only restricted lineages even in a steady state. While this restriction could reflect heterogeneity in the developmental potential of HSCs, we propose an alternative model in which the BM microenvironment is mosaic in supporting commitment of progenitors toward distinct lineages. Our computer simulation based on this model successfully recapitulated the observed clinical data. STEM CELLS 2013;31:536-546 Disclosure of potential conflicts of interest is found at the end of this article.

Whole transcriptome sequencing identifies increased CXCR2 expression in PNH granulocytes

“…GPI-AP À cells are far more frequent in the myeloid than in the lmphoid compartment. (Katagiri et al, 2013). Proportions of GPI-AP À cells were significantly higher in granulocytes than in HSCs ( Figure S5), and our data suggested that higher CXCR2 expression might explain the dominance of GPI-AP À cells in myeloid cells in PNH.…”

“…As CXCR2 ligands affect NF-κB activation in various cancer cells and promote cell survival, elevated CXCR2 level in GPI-AP − granulocytes might also represent a growth advantage. GPI-AP − cell prevalence is high in myeloid cells and low in lymphoid cells (Katagiri, et al 2013). Proportions of GPI-AP − cells were significantly higher in granulocytes than in HSCs (Fig S5), and our data suggested that higher CXCR2 expression might explain the dominance of GPI-AP − cells in myeloid cells in PNH.…”

“…PNH is an acquired clonal disorder that arises from haematopoietic stem cells (HSCs) and is caused by somatic mutations of the X-linked phosphatidylinositol glycan class A gene ( PIGA ), which results in global deficiency in cell surface expression of glycosyl phosphatidylinositol-anchored proteins (GPI-APs) (Takeda, et al 1993). GPI-AP deficiency is manifest in cells of multiple haematopoietic lineages (Katagiri, et al 2013). PNH is clinically closely related to aplastic anaemia (AA), and occurs almost exclusively in bone marrow (BM) failure associated with favourable outcome to immunosuppressive therapy (Young, et al 2006).…”

T Cell Transcriptomes from Paroxysmal Nocturnal Hemoglobinuria Patients Reveal Novel Signaling Pathways

“…However, duration of prior IST from sampling date was quite long, and immunosuppressive therapies were not being administered to any patient at the time of sampling. GPI-AP - T cells were not examined, due to the low frequency of this population (78). As our T cells were unstimulated, it is possible that we failed to detect difference in gene expression apparent only on activation.…”

A population of CD20+CD27+CD43+CD38lo/int B1 cells in PNH are missing GPI-anchored proteins and harbor PIGA mutations

“…16 The proportion of FLAER 2 PNH cells in each cell population varied among the first samples taken from all 6 patients, consistent with previous reports. [17][18][19] Granulocytes and monocytes had the highest proportions of FLAER 2 cells in all 6 patients (ranges, 68.5% to 100% and 75.3% to 100%, respectively; Figure 1C; supplemental Table 3). The absolute number of B1 cells varied among the samples and ranged from 2.17 3 10 6 /L to 14.52 3 10 6 /L ( Figure 1D; supplemental Table 4).…”