The evolution of cellular deficiency in GATA2 mutation

Research output: Contribution to journalArticlepeer-review

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The evolution of cellular deficiency in GATA2 mutation. / Dickinson, Rachel E; Milne, Paul; Jardine, Laura; Zandi, Sasan; Swierczek, Sabina I; McGovern, Naomi; Cookson, Sharon; Ferozepurwalla, Zaveyna; Langridge, Alexander; Pagan, Sarah; Gennery, Andrew; Heiskanen-Kosma, Tarja; Hämäläinen, Sari; Seppänen, Mikko; Helbert, Matthew; Tholouli, Eleni; Gambineri, Eleonora; Reykdal, Sigrún; Gottfreðsson, Magnús; Thaventhiran, James E; Morris, Emma; Hirschfield, Gideon; Richter, Alex G; Jolles, Stephen; Bacon, Chris M; Hambleton, Sophie; Haniffa, Muzlifah; Bryceson, Yenan; Allen, Carl; Prchal, Josef T; Dick, John E; Bigley, Venetia; Collin, Matthew.

In: Blood, Vol. 123, No. 6, 06.02.2014, p. 863-74.

Research output: Contribution to journalArticlepeer-review

Harvard

Dickinson, RE, Milne, P, Jardine, L, Zandi, S, Swierczek, SI, 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, Thaventhiran, JE, Morris, E, Hirschfield, G, Richter, AG, Jolles, S, Bacon, CM, Hambleton, S, Haniffa, M, Bryceson, Y, Allen, C, Prchal, JT, Dick, JE, Bigley, V & Collin, M 2014, 'The evolution of cellular deficiency in GATA2 mutation', Blood, vol. 123, no. 6, pp. 863-74. https://doi.org/10.1182/blood-2013-07-517151

APA

Dickinson, R. E., Milne, P., Jardine, L., Zandi, S., Swierczek, S. I., 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., ... Collin, M. (2014). The evolution of cellular deficiency in GATA2 mutation. Blood, 123(6), 863-74. https://doi.org/10.1182/blood-2013-07-517151

Vancouver

Dickinson RE, Milne P, Jardine L, Zandi S, Swierczek SI, McGovern N et al. The evolution of cellular deficiency in GATA2 mutation. Blood. 2014 Feb 6;123(6):863-74. https://doi.org/10.1182/blood-2013-07-517151

Author

Dickinson, Rachel E ; Milne, Paul ; Jardine, Laura ; Zandi, Sasan ; Swierczek, Sabina I ; McGovern, Naomi ; Cookson, Sharon ; Ferozepurwalla, Zaveyna ; Langridge, Alexander ; Pagan, Sarah ; Gennery, Andrew ; Heiskanen-Kosma, Tarja ; Hämäläinen, Sari ; Seppänen, Mikko ; Helbert, Matthew ; Tholouli, Eleni ; Gambineri, Eleonora ; Reykdal, Sigrún ; Gottfreðsson, Magnús ; Thaventhiran, James E ; Morris, Emma ; Hirschfield, Gideon ; Richter, Alex G ; Jolles, Stephen ; Bacon, Chris M ; Hambleton, Sophie ; Haniffa, Muzlifah ; Bryceson, Yenan ; Allen, Carl ; Prchal, Josef T ; Dick, John E ; Bigley, Venetia ; Collin, Matthew. / The evolution of cellular deficiency in GATA2 mutation. In: Blood. 2014 ; Vol. 123, No. 6. pp. 863-74.

Bibtex

@article{ab9c4e6166d4459cb039663814616d82,
title = "The evolution of cellular deficiency in GATA2 mutation",
abstract = "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, na{\"i}ve 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.",
keywords = "Adolescent, Adult, Aged, Aged, 80 and over, B-Lymphocytes, Biomarkers, Case-Control Studies, Child, Child, Preschool, Clonal Evolution, Cross-Sectional Studies, Dendritic Cells, Enzyme-Linked Immunosorbent Assay, Female, Follow-Up Studies, GATA2 Transcription Factor, Genetic Association Studies, Humans, Killer Cells, Natural, Male, Middle Aged, Monocytes, Mutation, Myelodysplastic Syndromes, Pedigree, Prognosis, Young Adult, fms-Like Tyrosine Kinase 3",
author = "Dickinson, {Rachel E} and Paul Milne and Laura Jardine and Sasan Zandi and Swierczek, {Sabina I} and Naomi McGovern and Sharon Cookson and Zaveyna Ferozepurwalla and Alexander Langridge and Sarah Pagan and Andrew Gennery and Tarja Heiskanen-Kosma and Sari H{\"a}m{\"a}l{\"a}inen and Mikko Sepp{\"a}nen and Matthew Helbert and Eleni Tholouli and Eleonora Gambineri and Sigr{\'u}n Reykdal and Magn{\'u}s Gottfre{\dh}sson and Thaventhiran, {James E} and Emma Morris and Gideon Hirschfield and Richter, {Alex G} and Stephen Jolles and Bacon, {Chris M} and Sophie Hambleton and Muzlifah Haniffa and Yenan Bryceson and Carl Allen and Prchal, {Josef T} and Dick, {John E} and Venetia Bigley and Matthew Collin",
year = "2014",
month = feb,
day = "6",
doi = "10.1182/blood-2013-07-517151",
language = "English",
volume = "123",
pages = "863--74",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "6",

}

RIS

TY - JOUR

T1 - The evolution of cellular deficiency in GATA2 mutation

AU - Dickinson, Rachel E

AU - Milne, Paul

AU - Jardine, Laura

AU - Zandi, Sasan

AU - Swierczek, Sabina I

AU - McGovern, Naomi

AU - Cookson, Sharon

AU - Ferozepurwalla, Zaveyna

AU - Langridge, Alexander

AU - Pagan, Sarah

AU - Gennery, Andrew

AU - Heiskanen-Kosma, Tarja

AU - Hämäläinen, Sari

AU - Seppänen, Mikko

AU - Helbert, Matthew

AU - Tholouli, Eleni

AU - Gambineri, Eleonora

AU - Reykdal, Sigrún

AU - Gottfreðsson, Magnús

AU - Thaventhiran, James E

AU - Morris, Emma

AU - Hirschfield, Gideon

AU - Richter, Alex G

AU - Jolles, Stephen

AU - Bacon, Chris M

AU - Hambleton, Sophie

AU - Haniffa, Muzlifah

AU - Bryceson, Yenan

AU - Allen, Carl

AU - Prchal, Josef T

AU - Dick, John E

AU - Bigley, Venetia

AU - Collin, Matthew

PY - 2014/2/6

Y1 - 2014/2/6

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - B-Lymphocytes

KW - Biomarkers

KW - Case-Control Studies

KW - Child

KW - Child, Preschool

KW - Clonal Evolution

KW - Cross-Sectional Studies

KW - Dendritic Cells

KW - Enzyme-Linked Immunosorbent Assay

KW - Female

KW - Follow-Up Studies

KW - GATA2 Transcription Factor

KW - Genetic Association Studies

KW - Humans

KW - Killer Cells, Natural

KW - Male

KW - Middle Aged

KW - Monocytes

KW - Mutation

KW - Myelodysplastic Syndromes

KW - Pedigree

KW - Prognosis

KW - Young Adult

KW - fms-Like Tyrosine Kinase 3

U2 - 10.1182/blood-2013-07-517151

DO - 10.1182/blood-2013-07-517151

M3 - Article

C2 - 24345756

VL - 123

SP - 863

EP - 874

JO - Blood

JF - Blood

SN - 0006-4971

IS - 6

ER -