The small population of PIG-A mutant cells in myelodysplastic syndromes do not arise from multipotent hematopoietic stem cells.

Abstract

BACKGROUND:

Patients with paroxysmal nocturnal hemoglobinuria harbor clonal glycosylphosphatidylinositol-anchor deficient cells arising from a multipotent hematopoietic stem cell acquiring a PIG-A mutation. Many patients with aplastic anemia and myelodysplastic syndromes also harbor small populations of glycosylphosphatidylinositol-anchor deficient cells. Patients with aplastic anemia often evolve into paroxysmal nocturnal hemoglobinuria; however, myelodysplastic syndromes seldom evolve into paroxysmal nocturnal hemoglobinuria. Here, we investigate the origin and clonality of small glycosylphosphatidylinositol-anchor deficient cell populations in aplastic anemia and myelodysplastic syndromes.

DESIGN AND METHODS:

We used peripheral blood flow cytometry to identify glycosylphosphatidylinositol-anchor deficient blood cells, a proaerolysin-resistant colony forming cell assay to select glycosylphosphatidylinositol-anchor deficient progenitor cells, a novel T-lymphocyte enrichment culture assay with proaerolysin selection to expand glycosylphosphatidylinositol-anchor deficient T lymphocytes, and PIG-A gene sequencing assays to identify and analyze PIG-A mutations in patients with aplastic anemia and myelodysplastic syndromes.

RESULTS:

Twelve of 15 aplastic anemia patients were found to harbor a small population of glycosylphosphatidylinositol-anchor deficient granulocytes; 11 of them were found to harbor a small population of glycosylphosphatidylinositol-anchor deficient erythrocytes, 10 patients were detected to harbor glycosylphosphatidylinositol-anchor deficient T lymphocytes, and 3 of them were detected only after T-lymphocyte enrichment in proaerolysin selection. PIG-A mutation analyses on 3 patients showed that all of them harbored a matching PIG-A mutation between CFU-GM and enriched T lymphocytes. Two of 26 myelodysplastic syndromes were found to harbor small populations of glycosylphosphatidylinositol-anchor deficient granulocytes and erythrocytes transiently. Bone marrow derived CD34(+) cells from 4 patients grew proaerolysin-resistant colony forming cells bearing PIG-A mutations. No glycosylphosphatidylinositol-anchor deficient T lymphocytes were detected in myelodysplastic syndrome patients.

CONCLUSIONS:

In contrast to aplastic anemia and paroxysmal nocturnal hemoglobinuria, where PIG-A mutations arise from multipotent hematopoietic stem cells, glycosylphosphatidylinositol-anchor deficient cells in myelodysplastic syndromes appear to arise from more committed progenitors.

• Authors: Jeffrey J Pu, Rong Hu, Galina L Mukhina, Hetty E Carraway, Michael A McDevitt, Robert A Brodsky
• Journal: Haematologica (Haematologica) Vol. 97 Issue 8 Pg. 1225-33 (Aug 2012) ISSN: 1592-8721 [Electronic] Italy
• PMID: 22315493 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Membrane Proteins
• phosphatidylinositol glycan-class A protein

Topics

• Adult
• Aged
• Anemia, Aplastic (genetics, metabolism)
• Female
• Flow Cytometry
• Hematopoietic Stem Cells (metabolism)
• Hemoglobinuria, Paroxysmal (genetics, metabolism)
• Humans
• Male
• Membrane Proteins (genetics, metabolism)
• Middle Aged
• Mutation
• Myelodysplastic Syndromes (genetics, metabolism)
• T-Lymphocytes (metabolism)
• Young Adult