The evolution of cellular deficiency in GATA2 mutation
| Autor: | Re, Dickinson, Milne P, Jardine L, Zandi S, Si, Swierczek, McGovern N, Cookson S, Ferozepurwalla Z, Langridge A, Pagan S, Gennery A, Heiskanen-Kosma T, Hämäläinen S, Seppänen M, Helbert M, Tholouli E, Gambineri E, Reykdal S, Gottfreðsson M, Je, Thaventhiran, Morris E, Hirschfield G, Ag, Richter, Jolles S, Cm, Bacon, Hambleton S, Haniffa M, Yenan Bryceson, Allen C, Jt, Prchal, Je, Dick, Bigley V, Collin M |
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| Rok vydání: | 2013 |
| Předmět: |
Adult
Male Adolescent Hematopoiesis and Stem Cells Enzyme-Linked Immunosorbent Assay Monocytes Clonal Evolution Young Adult fluids and secretions hemic and lymphatic diseases Humans Child Genetic Association Studies Aged Aged 80 and over B-Lymphocytes hemic and immune systems Dendritic Cells Middle Aged Prognosis Pedigree GATA2 Transcription Factor Killer Cells Natural Cross-Sectional Studies fms-Like Tyrosine Kinase 3 Case-Control Studies Child Preschool Myelodysplastic Syndromes embryonic structures Mutation Female Biomarkers Follow-Up Studies |
| Zdroj: | Europe PubMed Central |
| ISSN: | 1528-0020 |
| Popis: | Constitutive heterozygous GATA2 mutation is associated with deafness, lymphedema, mononuclear cytopenias, infection, myelodysplasia (MDS), and acute myeloid leukemia. In this study, we describe a cross-sectional analysis of 24 patients and 6 relatives with 14 different frameshift or substitution mutations of GATA2. A pattern of dendritic cell, monocyte, B, and natural killer (NK) lymphoid deficiency (DCML deficiency) with elevated Fms-like tyrosine kinase 3 ligand (Flt3L) was observed in all 20 patients phenotyped, including patients with Emberger syndrome, monocytopenia with Mycobacterium avium complex (MonoMAC), and MDS. Four unaffected relatives had a normal phenotype indicating that cellular deficiency may evolve over time or is incompletely penetrant, while 2 developed subclinical cytopenias or elevated Flt3L. Patients with GATA2 mutation maintained higher hemoglobin, neutrophils, and platelets and were younger than controls with acquired MDS and wild-type GATA2. Frameshift mutations were associated with earlier age of clinical presentation than substitution mutations. Elevated Flt3L, loss of bone marrow progenitors, and clonal myelopoiesis were early signs of disease evolution. Clinical progression was associated with increasingly elevated Flt3L, depletion of transitional B cells, CD56(bright) NK cells, naïve T cells, and accumulation of terminally differentiated NK and CD8(+) memory T cells. These studies provide a framework for clinical and laboratory monitoring of patients with GATA2 mutation and may inform therapeutic decision-making. |
| Databáze: | OpenAIRE |
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