GATA2 deficiency and related myeloid neoplasms

The GATA2 gene codes for a hematopoietic transcription factor that through its two zinc fingers (ZF) can occupy GATA-DNA motifs in a countless number of genes. It is crucial for the proliferation and maintenance of hematopoietic stem cells. During the past 5 years, germline heterozygous mutations in GATA2 were reported in several hundred patients with various phenotypes ranging from mild cytopenia to severe immunodeficiency involving B cells, natural killer cells, CD4+ cells, monocytes and dendritic cells (MonoMAC/DCML), and myeloid neoplasia. Some patients additionally show syndromic features such as congenital deafness and lymphedema (originally defining the Emberger syndrome) or pulmonary disease and vascular problems. The common clinical denominator in all reported cohorts is the propensity for myeloid neoplasia (myelodysplastic syndrome [MDS], myeloproliferative neoplasms [MPN], chronic myelomonocytic leukemia [CMML], acute myeloid leukemia [AML]) with an overall prevalence of approximately 75% and a median age of onset of roughly 20 years. Three major mutational types are encountered in GATA2-deficient patients: truncating mutations prior to ZF2, missense mutations within ZF2, and noncoding variants in the +9.5kb regulatory region of GATA2. Recurrent somatic lesions comprise monosomy 7 and trisomy 8 karyotypes and mutations in SETBP1 and ASXL1 genes. The high risk for progression to advanced myeloid neoplasia and life-threatening infectious complications guide decision-making towards timely stem cell transplantation.

[1]  J. D. Engel,et al.  A remote GATA2 hematopoietic enhancer drives leukemogenesis in inv(3)(q21;q26) by activating EVI1 expression. , 2014, Cancer cell.

[2]  J. Fitzgibbon,et al.  Germ-line GATA2 p.THR354MET mutation in familial myelodysplastic syndrome with acquired monosomy 7 and ASXL1 mutation demonstrating rapid onset and poor survival , 2012, Haematologica.

[3]  E. Bresnick,et al.  Dynamic GATA Factor Interplay at a Multicomponent Regulatory Region of the GATA-2 Locus* , 2005, Journal of Biological Chemistry.

[4]  S. Miyano,et al.  GATA2 and secondary mutations in familial myelodysplastic syndromes and pediatric myeloid malignancies , 2015, Haematologica.

[5]  M. Wlodarski,et al.  Mutational landscape in children with myelodysplastic syndromes is distinct from adults: specific somatic drivers and novel germline variants , 2017, Leukemia.

[6]  S. Holland,et al.  GATA2 deficiency-associated bone marrow disorder differs from idiopathic aplastic anemia. , 2015, Blood.

[7]  R. Viger,et al.  Role of the GATA family of transcription factors in endocrine development, function, and disease. , 2008, Molecular endocrinology.

[8]  Elaine Dzierzak,et al.  GATA-2 Plays Two Functionally Distinct Roles during the Ontogeny of Hematopoietic Stem Cells , 2004, The Journal of experimental medicine.

[9]  J. Orange,et al.  GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. , 2014, Blood.

[10]  M. Wlodarski,et al.  Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents. , 2016, Blood.

[11]  A. Dutra,et al.  Myelodysplasia in autosomal dominant and sporadic monocytopenia immunodeficiency syndrome: diagnostic features and clinical implications , 2011, Haematologica.

[12]  S. Orkin,et al.  A Single cis Element Maintains Repression of the Key Developmental Regulator Gata2 , 2010, PLoS genetics.

[13]  Smita Y. Patel,et al.  Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. , 2011, Blood.

[14]  Jian-yong Li,et al.  GATA-2 L359 V mutation is exclusively associated with CML progression but not other hematological malignancies and GATA-2 P250A is a novel single nucleotide polymorphism. , 2009, Leukemia research.

[15]  N. McGovern,et al.  The human syndrome of dendritic cell, monocyte, B and NK lymphoid deficiency , 2011, The Journal of experimental medicine.

[16]  S. Orkin,et al.  Human transcription factor GATA-2. Evidence for regulation of preproendothelin-1 gene expression in endothelial cells. , 1992, The Journal of biological chemistry.

[17]  Roberta Spinelli,et al.  Recurrent SETBP1 mutations in atypical chronic myeloid leukemia , 2012, Nature Genetics.

[18]  M. Horwitz.  GATA2 deficiency: flesh and blood. , 2014, Blood.

[19]  C. Mueller,et al.  GATA-4/5/6, a subfamily of three transcription factors transcribed in developing heart and gut. , 1994, The Journal of biological chemistry.

[20]  Thomas E. Hughes,et al.  Nonmyeloablative allogeneic hematopoietic stem cell transplantation for GATA2 deficiency. , 2014, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[21]  T. Kalina,et al.  Loss of B cells and their precursors is the most constant feature of GATA-2 deficiency in childhood myelodysplastic syndrome , 2016, Haematologica.

[22]  A. Kohlmann,et al.  GATA2 mutations are frequent in intermediate-risk karyotype AML with biallelic CEBPA mutations and are associated with favorable prognosis , 2013, Leukemia.

[23]  Saijuan Chen,et al.  Gain-of-function mutation of GATA-2 in acute myeloid transformation of chronic myeloid leukemia , 2008, Proceedings of the National Academy of Sciences.

[24]  Stuart H. Orkin,et al.  An early haematopoietic defect in mice lacking the transcription factor GATA-2 , 1994, Nature.

[25]  G. Blobel,et al.  Distinct Functions of Dispersed GATA Factor Complexes at an Endogenous Gene Locus , 2006, Molecular and Cellular Biology.

[26]  V. Bigley,et al.  Haematopoietic and immune defects associated with GATA2 mutation , 2015, British journal of haematology.

[27]  J. Ernerudh,et al.  The inverted CD4/CD8 ratio and associated parameters in 66-year-old individuals: the Swedish HEXA immune study , 2012, AGE.

[28]  David A. Williams,et al.  Genomic analysis of bone marrow failure and myelodysplastic syndromes reveals phenotypic and diagnostic complexity , 2015, Haematologica.

[29]  U. Jäger,et al.  Transcription factor GATA-2 gene is located near 3q21 breakpoints in myeloid leukemia. , 2000, Biochemical and biophysical research communications.

[30]  O. Abdel-Wahab,et al.  Collaborating constitutive and somatic genetic events in myeloid malignancies: ASXL1 mutations in patients with germline GATA2 mutations , 2014, Haematologica.

[31]  M. Odero,et al.  Overexpression of GATA2 predicts an adverse prognosis for patients with acute myeloid leukemia and it is associated with distinct molecular abnormalities , 2012, Leukemia.

[32]  S. Holland,et al.  Successful allogeneic hematopoietic stem cell transplantation for GATA2 deficiency. , 2011, Blood.

[33]  Sahar Mansour,et al.  Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome) , 2011, Nature Genetics.

[34]  Tariq Enver,et al.  Haploinsufficiency of GATA-2 perturbs adult hematopoietic stem-cell homeostasis. , 2005, Blood.

[35]  N. McGovern,et al.  The evolution of cellular deficiency in GATA2 mutation. , 2014, Blood.

[36]  S. Orkin,et al.  Transcription factor GATA-2 is required for proliferation/survival of early hematopoietic cells and mast cell formation, but not for erythroid and myeloid terminal differentiation. , 1997, Blood.

[37]  M. Wlodarski,et al.  Clonal Mutational Landscape of Childhood Myelodysplastic Syndromes , 2015 .

[38]  Christopher A. Miller,et al.  Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia. , 2015, Blood.

[39]  P. Rohrlich,et al.  High frequency of GATA2 mutations in patients with mild chronic neutropenia evolving to MonoMac syndrome, myelodysplasia, and acute myeloid leukemia. , 2013, Blood.

[40]  J. Tchinda,et al.  Somatic Genetic and Epigenetic Architecture of Myelodysplastic Syndromes Arising from GATA2 Deficiency , 2015 .

[41]  S. Nishikawa,et al.  Expression and domain-specific function of GATA-2 during differentiation of the hematopoietic precursor cells in midgestation mouse embryos. , 2003, Blood.

[42]  Colin N. Dewey,et al.  Gata2 cis-element is required for hematopoietic stem cell generation in the mammalian embryo , 2013, The Journal of experimental medicine.

[43]  H. Aburatani,et al.  GATA factor switching from GATA2 to GATA1 contributes to erythroid differentiation , 2013, Genes to cells : devoted to molecular & cellular mechanisms.

[44]  Q. Wang,et al.  Exome sequencing identifies highly recurrent somatic GATA2 and CEBPA mutations in acute erythroid leukemia , 2015, Leukemia.

[45]  J. D. Engel,et al.  GATA factor activity is required for the trophoblast-specific transcriptional regulation of the mouse placental lactogen I gene. , 1994, Development.

[46]  Y Fujiwara,et al.  Expression and genetic interaction of transcription factors GATA-2 and GATA-3 during development of the mouse central nervous system. , 1999, Developmental biology.

[47]  S. Holland,et al.  Spectrum of myeloid neoplasms and immune deficiency associated with germline GATA2 mutations , 2015, Cancer medicine.

[48]  J. D. Engel,et al.  The mouse GATA-2 gene is expressed in the para-aortic splanchnopleura and aorta-gonads and mesonephros region. , 1999, Blood.

[49]  T. Naoe,et al.  GATA2 zinc finger 2 mutation found in acute myeloid leukemia impairs myeloid differentiation. , 2013, Leukemia research reports.

[50]  Y. Akine,et al.  Identification of human GATA-2 gene distal IS exon and its expression in hematopoietic stem cell fractions. , 2000, Journal of biochemistry.

[51]  T. Vulliamy,et al.  Marked genetic heterogeneity in familial myelodysplasia/acute myeloid leukaemia , 2012, British journal of haematology.

[52]  G. Mufti,et al.  Emberger syndrome—Primary lymphedema with myelodysplasia: Report of seven new cases , 2010, American journal of medical genetics. Part A.

[53]  M. Odero,et al.  GATA2 Germline Mutations Impair GATA2 Transcription, Causing Haploinsufficiency: Functional Analysis of the p.Arg396Gln Mutation , 2015, The Journal of Immunology.

[54]  Kirby D. Johnson,et al.  GATA2 haploinsufficiency caused by mutations in a conserved intronic element leads to MonoMAC syndrome. , 2013, Blood.

[55]  V. Bigley,et al.  Dendritic cell, monocyte, B and NK lymphoid deficiency defines the lost lineages of a new GATA-2 dependent myelodysplastic syndrome , 2011, Haematologica.

[56]  Bernard Keavney,et al.  Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency. , 2011, Blood.

[57]  Anna L. Brown,et al.  Heritable GATA2 Mutations Associated with Familial Myelodysplastic Syndrome and Acute Myeloid Leukemia , 2011, Nature Genetics.

[58]  J. Rosenfeld,et al.  Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature. , 2012, Blood.

[59]  S. Holland,et al.  Adaptive NK cells can persist in patients with GATA2 mutation depleted of stem and progenitor cells. , 2017, Blood.

[60]  S. Nakazawa,et al.  The expression pattern of erythrocyte/megakaryocyte-related transcription factors GATA-1 and the stem cell leukemia gene correlates with hematopoietic differentiation and is associated with outcome of acute myeloid leukemia. , 1995, Blood.

[61]  O. Ohara,et al.  Successful reduced‐intensity stem cell transplantation for GATA2 deficiency before progression of advanced MDS , 2016, Pediatric transplantation.

[62]  M. Wlodarski,et al.  Unexpected High Frequency of GATA2 Mutations in Children with Non-Familial MDS and Monosomy 7 , 2012 .

[63]  S. Miyano,et al.  Somatic SETBP1 mutations in myeloid malignancies , 2013, Nature Genetics.

[64]  S. Holland,et al.  Acquired ASXL1 mutations are common in patients with inherited GATA2 mutations and correlate with myeloid transformation , 2014, Haematologica.

[65]  E. Hoster,et al.  GATA2 zinc finger 1 mutations associated with biallelic CEBPA mutations define a unique genetic entity of acute myeloid leukemia. , 2012, Blood.

[66]  Britta A. M. Bouwman,et al.  A Single Oncogenic Enhancer Rearrangement Causes Concomitant EVI1 and GATA2 Deregulation in Leukemia , 2014, Cell.