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

Pu, Jeffrey J.; Hu, Rong; Mukhina, Galina L.; Carraway, Hetty E.; McDevitt, Michael A.

doi:10.3324/haematol.2011.048215

Cited by 21 publications

(20 citation statements)

References 37 publications

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“…In AA and PNH, GPI‐AP deficient cells in arise from a multipotent HSC; PIG‐A mutations in these patients are clonal and affect all hematopoietic lineages, including T cells. In contrast, GPI‐AP deficient cells that can be detected either in healthy controls or patients with MDS arise from colony forming cells (CFC); the PIG‐A mutations in these individuals are transient, non‐clonal, and do not involve T cells . These studies demonstrate fundamental differences between AA and MDS and help explain why PNH may arise from AA but not from MDS.…”

Section: Interpretation Of Pnh Testing Resultsmentioning

confidence: 94%

“…These studies demonstrate fundamental differences between AA and MDS and help explain why PNH may arise from AA but not from MDS. Furthermore, in healthy controls the PIG‐A mutation rate in CFC assays was demonstrated to be about 1 in 50,000 (∼ 0.002%) while that of PNH RBC phenotypes is 2–6 per million (i.e., 0.002–0.006%) in fresh PB of normal individuals. Thus, for diagnostic purposes, a threshold of 0.01%, which represents a level about 5–10X above that ever detected in healthy controls appears to be clinically reasonable threshold to define a disease‐related PNH clone .…”

Section: Interpretation Of Pnh Testing Resultsmentioning

confidence: 99%

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ICCS/ESCCA Consensus Guidelines to detect GPI‐deficient cells in Paroxysmal Nocturnal Hemoglobinuria (PNH) and related Disorders Part 1 – Clinical Utility

DeZern

Borowitz

2018

Cytometry Part B Clinical

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Paroxysmal nocturnal hemoglobinuria (PNH) arises as a consequence of the non-malignant clonal expansion of one or more hematopoietic stem cells with an acquired somatic mutation of the PIGA gene (Brodsky RA. Blood 113 (2009) 6522-6527). Progeny of affected stem cells are deficient in glycosyl phosphatidylinositol-anchored proteins (GPI-APs). This deficiency is readily detected by flow cytometry. Though this seems straightforward, the clinical utility of this testing requires that the ordering clinician understand not only the characteristics of the test, but also the biology of the underlying disease, and the clinical and laboratory manifestations in the individual patient. When interpreted correctly, the results from PNH flow cytometry testing, including presence and size of the clonal populations and the cell types involved, can allow the clinician to classify the disease appropriately; evaluate the risk of disease progression; and subsequently monitor response to therapy. In these guidelines, we discuss the evaluation of a patient with suspected PNH or other bone marrow failure disorders, with specific emphasis on the contribution of this testing to the diagnosis, classification, and monitoring of patients. For convenience we will commonly refer to these flow cytometry studies as "PNH testing" recognizing that an abnormal result is not diagnostic of PNH; rather both laboratory and clinical features are used to establish this diagnosis. V C 2017 International Clinical Cytometry Society

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Section: Interpretation Of Pnh Testing Resultsmentioning

confidence: 94%

Section: Interpretation Of Pnh Testing Resultsmentioning

confidence: 99%

ICCS/ESCCA Consensus Guidelines to detect GPI‐deficient cells in Paroxysmal Nocturnal Hemoglobinuria (PNH) and related Disorders Part 1 – Clinical Utility

DeZern

Borowitz

2018

Cytometry Part B Clinical

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“…The culture dishes were scored for BFU-Es under an inverted phase contrast microscope and reported as an average of the 3 dishes in BFU-E per 1 × 10 5 nucleated cells. Colony identification was performed with greater than 50 cells identified as a BFU-E (Pu, Hu et al 2012). As this was performed as a standardized assay in a CLIA certified lab, only enumeration of the colonies was performed.…”

Section: Methodsmentioning

confidence: 99%

Burst-forming unit–erythroid assays to distinguish cellular bone marrow failure disorders

DeZern

McDevitt

et al. 2013

Experimental Hematology

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Patients with cytopenias and a cellular bone marrow can be a diagnostic and a therapeutic challenge. Previous reports have suggested a role for progenitor assays as a potentially useful test for diagnosis and predicting response to therapy. Here we report the results of BFU-E assays in 48 consultative cases of single or multi-lineage cytopenias with cellular marrows. The final diagnoses included 17 patients with myelodysplastic syndrome (MDS); 9 patients with pure red cell aplasia (PRCA) [non-large granular lymphocytosis (LGL) in etiology]; 15 patients with LGL (8 of which had a single lineage cytopenia only while the other 7 had multi-lineage cytopenias); and 7 patients with cytopenias associated with systemic inflammation related to autoimmune conditions. In this cohort, nonmalignant diseases were well-distinguished from MDS by BFU-E growth. Our data suggest that low BFU-E growth (less than 10 BFU-E /105 marrow mononuclear cells) helps to exclude LGL, PRCA, or cytopenias associated with systemic inflammation as a cause of pancytopenia with a sensitivity of 96.8%, specificity of 76.5% and a predictive value of 88.2% (p=0.0001). BFU-E growth was also examined to predict response to treatment. Of the 29 patients in this cohort treated with immunosuppressive therapy across all disease groups, there was an 86% response rate with 25 responders (11 PRs and 14 CRs) and 4 non-responders. This did correlate with higher BFU-E growth. Our results suggest BFU-E assays are a useful adjunct in the diagnosis and management of cytopenias in the setting of a normocellular or hypercellular bone marrows.

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“…Jeśli do mutacji dochodzi w komórkach na wyższym poziomie rozwoju, na przykład jednostek tworzących kolonie (CFU, colony forming unit), jak ma to miejsce u zdrowych osób i niektórych pacjentów z MDS, to ze względu na brak możliwości samoodtwarzania defektywny klon zanika [7,32,33]. W związku z częstym występowaniem klonu PNH u chorych na AA zaczęto od poszukiwania związku między tymi dwiema chorobami.…”

Section: Klasyfikacja Z Uwzględnieniem Historii Naturalnej Chorobyunclassified

Nowe spojrzenie na nocną napadową hemoglobinurię

Piekarska

Spychalska

2015

Hematologia

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

Cited by 21 publications

References 37 publications

ICCS/ESCCA Consensus Guidelines to detect GPI‐deficient cells in Paroxysmal Nocturnal Hemoglobinuria (PNH) and related Disorders Part 1 – Clinical Utility

ICCS/ESCCA Consensus Guidelines to detect GPI‐deficient cells in Paroxysmal Nocturnal Hemoglobinuria (PNH) and related Disorders Part 1 – Clinical Utility

Burst-forming unit–erythroid assays to distinguish cellular bone marrow failure disorders

Nowe spojrzenie na nocną napadową hemoglobinurię

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