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GATA2 Germline Mutations Impair GATA2 Transcription, Causing Haploinsufficiency: Functional Analysis of the p.Arg396Gln Mutation This information is current as of September 28, 2021. Xabier Cortés-Lavaud, Manuel F. Landecho, Miren Maicas, Leire Urquiza, Juana Merino, Isabel Moreno-Miralles and María D. Odero J Immunol 2015; 194:2190-2198; Prepublished online 26 January 2015; Downloaded from doi: 10.4049/jimmunol.1401868 http://www.jimmunol.org/content/194/5/2190 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2015/01/23/jimmunol.140186 Material 8.DCSupplemental References This article cites 29 articles, 14 of which you can access for free at: http://www.jimmunol.org/content/194/5/2190.full#ref-list-1 Why The JI? Submit online. by guest on September 28, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology GATA2 Germline Mutations Impair GATA2 Transcription, Causing Haploinsufficiency: Functional Analysis of the p.Arg396Gln Mutation Xabier Corte´s-Lavaud,*,†,1 Manuel F. Landecho,‡,1 Miren Maicas,* Leire Urquiza,* Juana Merino,x Isabel Moreno-Miralles,* and Marı´a D. Odero*,† Germline GATA2 mutations have been identified as the cause of familial syndromes with immunodeficiency and predisposition to myeloid malignancies. GATA2 mutations appear to cause loss of function of the mutated allele leading to haploinsufficiency; however, this postulate has not been experimentally validated as the basis of these syndromes. We hypothesized that mutations that are translated into abnormal proteins could affect the transcription of GATA2, triggering GATA2 deficiency. Chromatin immunoprecipitation and luciferase assays showed that the human GATA2 protein activates its own transcription through Downloaded from a specific region located at 22.4 kb, whereas the p.Thr354Met, p.Thr355del, and p.Arg396Gln germline mutations impair GATA2 promoter activation. Accordingly, GATA2 expression was decreased to ∼58% in a patient with p.Arg396Gln, compared with controls. p.Arg396Gln is the second most common mutation in these syndromes, and no previous functional analyses have been performed. We therefore analyzed p.Arg396Gln. Our data show that p.Arg396Gln is a loss-of-function mutation affecting DNA- binding ability and, as a consequence, it fails to maintain the immature characteristics of hematopoietic stem and progenitor cells, which could result in defects in this cell compartment. In conclusion, we show that human GATA2 binds to its own promoter, http://www.jimmunol.org/ activating its transcription, and that the aforementioned mutations impair the transcription of GATA2. Our results indicate that they can affect other GATA2 target genes, which could partially explain the variability of symptoms in these diseases. Moreover, we show that p.Arg396Gln is a loss-of-function mutation, which is unable to retain the progenitor phenotype in cells where it is expressed. The Journal of Immunology, 2015, 194: 2190–2198. he GATA2 transcription factor has an essential role in the So far, 50 different germline GATA2 mutations have been re- proliferation and differentiation of hematopoietic cells (1). ported; most families display mutations that are located within the Recently, germline mutations in GATA2 have been iden- highly conserved C-terminal zinc finger (ZF) domain, and they T by guest on September 28, 2021 tified as the cause of familial syndromes with autosomal-dominant correspond to missense mutations (Supplemental Tables I, II). It inheritance that share common symptoms. Severe monocytopenia, has been reported that mutations in a conserved intronic enhancer NK and B lymphopenia, near absence of dendritic cells, and a pre- element lead to decreased GATA2 transcript levels, indicating the disposition to develop myelodysplastic syndrome, chronic myelo- necessity for both alleles to be functional to express the wild-type monocytic leukemia, and/or acute myeloid leukemia (AML) are (WT) phenotype, and suggesting GATA2 deficiency as the basis among the most prominent characteristics of these diseases (2–6). for these familial syndromes (7). In fact, Gata2+/2 mice express reduced levels of Gata2 in hematopoietic cells, and this has an impact on hematopoietic stem and progenitor cell (HSPC) ho- meostasis (8, 9). However, there is a considerable clinical het- *Hematology/Oncology Program, Center for Applied Medical Research, University erogeneity among patients (5), and GATA2 haploinsufficiency has of Navarra, Pamplona 31008, Spain; †Department of Biochemistry and Genetics, University of Navarra, Pamplona 31008, Spain; ‡Department of Internal Medicine, not been experimentally validated as the basis of these syndromes. University Clinic of Navarra, Navarra, Pamplona 31008, Spain; and xDepartment of We hypothesized that mutations affecting the C-terminal ZF, Immunology, University Clinic of Navarra, Pamplona 31008, Spain which are thought to allow production of a stable mRNA that is 1 X.C.-L. and M.F.L. contributed equally to this work. translated into an abnormal protein, could affect the transcription Received for publication July 22, 2014. Accepted for publication December 18, 2014. of GATA2, triggering GATA2 deficiency. In this study, we show This work was supported by Ministerio de Ciencia e Innovacio´n Grant PI11/02443, that the human GATA2 protein activates its own transcription and Departamento de Salud del Gobierno de Navarra Grant 78/2012, Instituto de Salud that three germline GATA2 mutations affecting the C-terminal ZF Carlos III–Red Tema´tica de Investigacio´n Contra el Ca´ncer Grant RD12/0036/0063, and by the Fundacio´n para Investigacio´nMe´dica Aplicada (Spain). impair GATA2 promoter activation. Moreover, we functionally ana- Address correspondence and reprint requests to Xabier Corte´s-Lavaud, Hematology/ lyze p.Arg396Gln, the second most common mutation in GATA2 Oncology Program, Center for Applied Medical Research, University of Navarra, deficiency syndromes, in the context of the clinical presentation of Avenida Pı´o XII 55, Pamplona 31008, Spain. E-mail address: [email protected] a patient with this mutation. The online version of this article contains supplemental material. Abbreviations used in this article: AML, acute myeloid leukemia; ATRA, all-trans Materials and Methods retinoic acid; ChIP, chromatin immunoprecipitation; G, granulocyte colony; GEMM, mixed colony; GM, granulocyte/macrophage colony; HSPC, hematopoietic stem and Cell lines and patient sample progenitor cell; IS, distal first exon; M, macrophage colony; MonoMAC, monocyto- penia and Mycobacterium avium complex infection; qPCR, quantitative PCR; qRT- HEL, TF1, MOLM13, and HeLa cell lines were cultured following the PCR, quantitative real-time RT-PCR; TPA, 12-O-tetradecanoylphorbol-13-acetate; German Collection of Microorganisms and Cell Cultures Cell Culture Bank TSS, transcription start site; WT, wild-type; ZF, zinc finger. recommendations (Braunschweig, Germany). Peripheral blood samples from patient and five healthy donors were obtained after written informed Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 consent by the University Clinic of Navarra. DNA was sequenced using www.jimmunol.org/cgi/doi/10.4049/jimmunol.1401868 The Journal of Immunology 2191 specific primers for each GATA2 exon in a 3500DX genetic analyzer (Life particles following the protocol used for HL60. Infected lineage2 mouse Technologies, Carlsbad, CA). PBMCs were extracted for analysis using the bone marrow cells (1.5 3 105) were plated into p100 plates with Metho- Ficoll protocol. Cult GF M3434 (StemCell Technologies, Vancouver, BC, Canada) for puromycin selection at 2 mg/ml for 10 d. For the second and third platings, RNA analysis 5.5 3 104 cells were plated for 10 d. The numbers of CFU were analyzed Total RNAwas extracted from freshly isolated PBMCs of individuals or cell 10 d after each plating, whereas CFU types were analyzed 10 d after the lines using the TRIzol reagent (Life Technologies). Quantitative real-time second plating. RT-PCR (qRT-PCR) was performed in the ABI Prism 7500 (Life Tech- Ethics statement nologies) using SYBR Green master mix or TaqMan master mix (Life Technologies) with specific primers (sequences are available upon request). The study has been approved by the Comisio´ndeE´ tica de Investigacio´nde HPRT1 or GAPDH expression was used as an internal control for SYBR or la Facultad de Medicina de la Universidad de Navarra (no. 037/2008). All TaqMan methods, respectively. Data were analyzed using the comparative animal studies were performed in accordance with the guidelines of the cycle threshold (DDCt) method. Animal Care Committee of the University of Navarra (no. 063/12). Chromatin immunoprecipitation and quantitative
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