High frequency of several PIG-A mutations in patients with aplastic anemia and myelodysplastic syndrome

Abstract

To clarify some characteristics of phosphatidylinositol glycanclass A gene (PIG-A) mutations in aplastic anemia (AA) and myelodysplastic syndrome (MDS) patients compared with those in paroxysmal nocturnal hemoglobinuria (PNH) patients, we investigated PIG-A mutations in CD59 À granulocytes and CD48 À monocytes from seven AA, eight MDS, and 11 PNH Japanese patients. The most frequent base or type abnormalities of the PIG-A gene in AA and MDS patients were base substitutions or missense mutations, respectively, and deletions or frameshift mutations, respectively, in PNH patients. Several PIG-A mutations, most of which were statistically minor, were found in glycosylphosphatidylinositol-negative cells from all AA and MDS patients but not from all PNH patients. However, the common PIG-A mutations during the clinical course between CD59 À granulocytes and/or CD48 À monocytes from each AA or MDS patient, except for Case 5, were not found. PIG-A mutations were different between the granulocytes and monocytes from five AA and five MDS patients. Our results indicate that there were some characteristics of PIG-A mutations in AA and MDS patients compared with PNH patients and that several minor PNH clones in these patients occurred at random during the clinical course. This partly explains the transformation of AA or MDS to PNH at intervals.

Differential gene expression of bone marrow-derived CD34+ cells is associated with survival of patients suffering from myelodysplastic syndrome

“…A broad variety of molecular changes like elevated Akt kinase phosphorylation [4], hyperactivation of the RAS signaling pathway [5] and mutations of the PIG-A [6] or JAK2 gene [7] have been found in patients with MDS. Still, most of the molecular pathology of MDS is unknown.…”

3′UTR-truncated Hmga2 cDNA causes MPN-like hematopoiesis by conferring a clonal growth advantage at the level of HSC in mice

“…1 The deficiency of GPI-linked proteins accounts for some features of the clinical phenotype such as intravascular hemolysis and hemoglobinuria but a major unanswered question concerns the mechanism underlying the clonal expansion of the mutated hematopoietic stem or early progenitor cell necessary for the development of disease. [2][3][4][5] A possible clue to the mechanism came from the observation that the HMGA2 gene was rearranged and the mRNA highly expressed, in the PNH cells of 2 patients, suggesting that in addition to the PIGA gene mutation an additional genetic event is required to confer a growth advantage to the PNH clone (two-hit-hypothesis). 6 We were thus interested in investigating the consequences of HMGA2 overexpression on hematopoiesis.…”

Low concentration of serum haptoglobin has impact on understanding complex pathophysiology in patients with acquired bone marrow failure syndromes

“…Immunofluorescent staining and flow cytometric analysis of CD59 expression on granulocytes and of CD48 expression on monocytes were performed using mouse monoclonal antibodies to CD59 labeled with fluorescein isothiocyanate (H19; IgG2a, j; RD PharMingen, San Diego, USA) and CD48 labeled with fluorescein isothiocyanate (14-57; IgG1; Immunotech, Marseille, France), respectively, according to the previous method [20,21] with a slight modification of the method of Wang et al [3]. Irrelevant monoclonal antibodies of the same subclasses were used as negative controls [14,[19][20][21].…”