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dc.contributor.authorDickinson, Rachel E
dc.contributor.authorMilne, Paul
dc.contributor.authorJardine, Laura
dc.contributor.authorZandi, Sasan
dc.contributor.authorSwierczek, Sabina I
dc.contributor.authorMcGovern, Naomi
dc.contributor.authorCookson, Sharon
dc.contributor.authorFerozepurwalla, Zaveyna
dc.contributor.authorLangridge, Alexander
dc.contributor.authorPagan, Sarah
dc.contributor.authorGennery, Andrew
dc.contributor.authorHeiskanen-Kosma, Tarja
dc.contributor.authorHämäläinen, Sari
dc.contributor.authorSeppänen, Mikko
dc.contributor.authorHelbert, Matthew
dc.contributor.authorTholouli, Eleni
dc.contributor.authorGambineri, Eleonora
dc.contributor.authorReykdal, Sigrún
dc.contributor.authorGottfreðsson, Magnús
dc.contributor.authorThaventhiran, James E
dc.contributor.authorMorris, Emma
dc.contributor.authorHirschfield, Gideon
dc.contributor.authorRichter, Alex G
dc.contributor.authorJolles, Stephen
dc.contributor.authorBacon, Chris M
dc.contributor.authorHambleton, Sophie
dc.contributor.authorHaniffa, Muzlifah
dc.contributor.authorBryceson, Yenan
dc.contributor.authorAllen, Carl
dc.contributor.authorPrchal, Josef T
dc.contributor.authorDick, John E
dc.contributor.authorBigley, Venetia
dc.contributor.authorCollin, Matthew
dc.date.accessioned2014-08-25T15:42:20Z
dc.date.available2014-08-25T15:42:20Z
dc.date.issued2014-02-06
dc.date.submitted2014
dc.identifier.citationBlood 2014, 123 (6):863-74en
dc.identifier.issn1528-0020
dc.identifier.pmid24345756
dc.identifier.doi10.1182/blood-2013-07-517151
dc.identifier.urihttp://hdl.handle.net/2336/325174
dc.descriptionTo access publisher's full text version of this article click on the hyperlink at the bottom of the pageen
dc.description.abstractConstitutive 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.
dc.description.sponsorshipLymphoma and Leukaemia Research British Society of Hematology Bright Red George Walker Trust Wellcome Trusten
dc.language.isoenen
dc.publisherAmer Soc Hematologyen
dc.relation.urlhttp://dx.doi.org/10.1182/blood-2013-07-517151en
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916878/en
dc.relation.urlhttp://www.bloodjournal.org/content/bloodjournal/123/6/863.full.pdfen
dc.rightsArchived with thanks to Blooden
dc.subjectFrumuren
dc.subjectArfgengien
dc.subjectBeinkrabbameinen
dc.subject.meshAdolescenten
dc.subject.meshAdulten
dc.subject.meshAgeden
dc.subject.meshAged, 80 and overen
dc.subject.meshB-Lymphocytes/immunologyen
dc.subject.meshBiological Markersen
dc.subject.meshCase-Control Studiesen
dc.subject.meshChilden
dc.subject.meshChild, Preschoolen
dc.subject.meshClonal Evolutionen
dc.subject.meshCross-Sectional Studiesen
dc.subject.meshDendritic Cells/immunologyen
dc.subject.meshEnzyme-Linked Immunosorbent Assayen
dc.subject.meshFemaleen
dc.subject.meshFollow-Up Studiesen
dc.subject.meshGATA2 Transcription Factor/genetics*en
dc.subject.meshGenetic Association Studiesen
dc.subject.meshHumansen
dc.subject.meshKiller Cells, Natural/immunologyen
dc.subject.meshMaleen
dc.subject.meshMiddle Ageden
dc.subject.meshMonocytes/immunologyen
dc.subject.meshMutation/genetics*en
dc.subject.meshMyelodysplastic Syndromes/blooden
dc.subject.meshPedigreeen
dc.subject.meshPrognosisen
dc.subject.meshYoung Adulten
dc.subject.meshfms-Like Tyrosine Kinase 3en
dc.subject.meshB-Lymphocytes/metabolismen
dc.subject.meshB-Lymphocytes/pathology*en
dc.subject.meshDendritic Cells/metabolismen
dc.subject.meshDendritic Cells/pathology*en
dc.subject.meshKiller Cells, Natural/metabolismen
dc.subject.meshKiller Cells, Natural/pathology*en
dc.subject.meshMonocytes/metabolismen
dc.subject.meshMonocytes/pathology*en
dc.subject.meshMyelodysplastic Syndromes/geneticsen
dc.subject.meshMyelodysplastic Syndromes/pathology*en
dc.subject.meshfms-Like Tyrosine Kinase 3/metabolismen
dc.titleThe evolution of cellular deficiency in GATA2 mutation.en
dc.typeArticleen
dc.contributor.departmentNewcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England, Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada, Univ Toronto, Dept Mol Genet, Toronto, ON, Canada, Univ Utah, Sch Med, Div Hematol, Salt Lake City, UT USA, Kuopio Univ Hosp, Dept Paediat, SF-70210 Kuopio, Finland, Helsinki Univ Cent Hosp, Div Infect Dis, Helsinki, Finland, Cent Manchester Univ Hosp, Dept Clin Immunol, Manchester, Lancs, England, Cent Manchester Univ Hosp, Dept Haematol, Manchester, Lancs, England, Univ Florence, Dept NEUROFARBA, Sect Childs Hlth, Dept Haematol Oncol,Anna Meyer Childrens Hosp, Florence, Italy , Univ Iceland, Fac Med, Sch Hlth Sci, Reykjavik, Iceland, Landspitali Univ Hosp, Dept Infect Dis, Reykjavik, Iceland, Cambridge Inst Med Res, Cambridge, England, UCL, UCL Inst Immun & Transplantat, London, England, Univ Hosp Birmingham, Dept Hepatol, Birmingham, W Midlands, England, Univ Hosp Birmingham, Dept Clin Immunol, Birmingham, W Midlands, England, Univ Wales Hosp, Dept Immunol, Cardiff CF4 4XW, S Glam, Wales, Newcastle Univ, Northern Ctr Canc Res, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England, Karolinska Inst, Ctr Infect Med, Stockholm, Sweden, Texas Childrens Canc Ctr, Dept Pediat, Houston, TX USAen
dc.identifier.journalBlooden
dc.rights.accessLandspitali Access - LSH-aðganguren
html.description.abstractConstitutive 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.


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