GATA2 GATA2 Germline Mutations Impair

Total Page:16

File Type:pdf, Size:1020Kb

GATA2 GATA2 Germline Mutations Impair 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
Recommended publications
  • Supplemental Material 1 (PDF)
    Supplementary Figure 1. Murine and human GATA2 promoter alignment shows highly conserved regions. Brackets delimit the highly conserved regions in both genomes, as graphics obtained from ECR Browser show: large areas marked in red indicate highly similar intergenic sequences, repetitive sequences in green, exonic sequences in yellow, and intronic sequences in salmon color. Horizontal axis represents base positions in the genome and the vertical axis represents the percentage identity between the human and mouse genomes. GATA2 binding sites are indicated in red within the brackets, and they were located using the TFSearch, Match and MatInspector transcription factor binding site finder algorithms. Comparison of GATA2 binding sites between both genomes and several surrounding nucleotides is shown in the middle, where GATA2 binding site core sequences are shown in italic and underlined. Two GATA2 binding sites at -2.8 belonged to a highly conserved region spanning 389 bp, with 87.7% homology with the human GATA2 promoter. Similarly, other two GATA2 binding sites at -1.8 were located within a 282 bp region with 75.5% homology. Additionally, a third 142 bp region was taken into account containing the -2992 GATA2 binding site, which showed 68.3% homology. Supplementary Table I: List of reported germline GATA2 mutations and associated syndromes. Mutation (DNA)* Affected exon Mutation (protein) Mutation type Affected ZF Reference Cases/families Associated syndrome c.1-200_871+527del2033 4, 5 p.Met1_Ser290del In-frame deletion None 4,7,20,S1 2/1
    [Show full text]
  • Nanoparticles to Upregulate Notch Signaling Victor
    Notch Intracellular Domain Plasmid Delivery via Poly(lactic-co-glycolic acid) Nanoparticles to Upregulate Notch Signaling Victoria L. Messerschmidt1,2†, Aneetta E. Kuriakose1,2†, Uday Chintapula1, Samantha Laboy1, Thuy Thi Dang Truong1, LeNaiya A. Kydd1, Justyn Jaworski1, Kytai T. Nguyen1,2*, Juhyun Lee1,2* 1Department of Bioengineering, University of Texas at Arlington, Arlington TX 76010 USA 2University of Texas Southwestern Medical Center, Dallas TX 75390 USA † These authors have contributed equally to this work Corresponding Author: Juhyun Lee, Ph.D. Joint Department of Bioengineering UT Arlington / UT Southwestern Arlington, TX 75022 Email: [email protected] Telephone: 817-272-6534 Fax: 817-272-2251 Abstract Notch signaling is a highly conserved signaling system that is required for embryonic development and regeneration of organs. When the signal is lost, maldevelopment occurs and leads to a lethal state. Liposomes and retroviruses are most commonly used to deliver genetic material to cells. However, there are many drawbacks to these systems such as increased toxicity, nonspecific delivery, short half-life, and stability after formulation. We utilized the negatively charged and FDA approved polymer poly(lactic-co-glycolic acid) to encapsulate Notch Intracellular Domain- containing plasmid in nanoparticles. In this study, we show that primary human umbilical vein endothelial cells readily uptake the nanoparticles with and without specific antibody targets. We demonstrated that our nanoparticles also are nontoxic, stable over time, and compatible with blood. We also determined that we can successfully transfect primary human umbilical vein endothelial cells (HUVECs) with our nanoparticles in static and dynamic environments. Lastly, we elucidated that our transfection upregulates the downstream genes of Notch signaling, indicating that the payload was viable and successfully altered the genetic downstream effects.
    [Show full text]
  • Lncegfl7os Regulates Human Angiogenesis by Interacting
    RESEARCH ARTICLE LncEGFL7OS regulates human angiogenesis by interacting with MAX at the EGFL7/miR-126 locus Qinbo Zhou1†, Bo Yu1†*, Chastain Anderson1, Zhan-Peng Huang2, Jakub Hanus1, Wensheng Zhang3, Yu Han4, Partha S Bhattacharjee5, Sathish Srinivasan6, Kun Zhang3, Da-zhi Wang2, Shusheng Wang1,7* 1Department of Cell and Molecular Biology, Tulane University, New Orleans, United States; 2Department of Cardiology, Boston Children’s Hospital, Harvard Medical School, Boston, United States; 3Department of Computer Science, Xavier University, New Orleans, United States; 4Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, United States; 5Department of Biology, Xavier University, New Orleans, United States; 6Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma, United States; 7Department of Ophthalmology, Tulane University, New Orleans, United States Abstract In an effort to identify human endothelial cell (EC)-enriched lncRNAs,~500 lncRNAs were shown to be highly restricted in primary human ECs. Among them, lncEGFL7OS, located in the opposite strand of the EGFL7/miR-126 gene, is regulated by ETS factors through a bidirectional promoter in ECs. It is enriched in highly vascularized human tissues, and upregulated in the hearts of dilated cardiomyopathy patients. LncEGFL7OS silencing impairs angiogenesis as shown by EC/fibroblast co-culture, in vitro/in vivo and ex vivo human choroid sprouting angiogenesis assays, while lncEGFL7OS overexpression has the opposite function. Mechanistically, *For correspondence: lncEGFL7OS is required for MAPK and AKT pathway activation by regulating EGFL7/miR-126 [email protected] (BY); expression. MAX protein was identified as a lncEGFL7OS-interacting protein that functions to [email protected] (SW) regulate histone acetylation in the EGFL7/miR-126 promoter/enhancer.
    [Show full text]
  • Letters to the Editor
    LETTERS TO THE EDITOR was discharged on long-term therapy with clar - + MonoMAC versus idiopathic CD4 lymphocytopenia . ithromycin, ethambutol, and rifampin. His skin lesions Comment to Haematologica. 2011;96(8):1221-5 resolved within a month of starting therapy. The cause of pancytopenia was initially thought to be due to BM sup - pression associated with disseminated MAC infection. We read with interest a recent article in Haematologica However, pancytopenia did not resolve and a BM biopsy describing a novel defined disorder known as MonoMAC was performed. This showed a markedly hypocellular (monocytopenia with Mycobacterium avium complex). 1 It is not infrequent for patients with MonoMAC to present with a low CD4 count, leading to a consideration of idio - pathic CD4-positive (CD4 +) lymphocytopenia (ICL). 2 Table 1. Summary of patient’s laboratory findings. Here we describe a case of MonoMAC who was initially Patient Reference range thought to have ICL and aplastic anemia. However, the combination of pancytopenia, profound monocytopenia, WBC 1.2 ¥10 9/L 4.1-10.9 ¥10 9/L and bone marrow (BM) findings support a diagnosis of Absolute neutrophil count 876 cells/ mL 1400-6500 cells/ mL MonoMAC. Absolute lymphocyte count 144 cells/ mL 1200-3400 cells/ mL A 24-year old Hispanic male presented with 2 ulcers on the lower extremities that he had had for two months. Absolute monocyte count 12 cells/ mL 300-820 cells/ mL These ulcers were 1.0 to 3.5 cm in size at their widest Hemoglobin 5.2 g/dL 14.0-18.0 g/dL point and had slightly raised erythematous borders with Hematocrit 16.2% 40-54% pink-glistening to black eschar bases (Figure 1A).
    [Show full text]
  • Targetome Analysis Revealed Involvement of Mir-126 in Neurotrophin Signaling Pathway: a Possible Role in Prevention of Glioma Development
    Original Article Targetome Analysis Revealed Involvement of MiR-126 in Neurotrophin Signaling Pathway: A Possible Role in Prevention of Glioma Development 1# 1, 2# 3 4, 5 Maedeh Rouigari, M.Sc. , Moein Dehbashi, Ph.D. , Kamran Ghaedi, Ph.D. , Meraj Pourhossein, Ph.D. * 1. Isfahan Neuroscience Research Center (INRC), Alzahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran 2. Genetics Division, Department of Biology, Faculty of Sciences, University of Isfahan, Isfahan, Iran 3. Cell and Molecular Biology Division, Department of Biology, Faculty of Sciences, University of Isfahan, Isfahan, Iran 4. Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences Isfahan, Iran 5. Department of Food Science and Technology, Food Security Research Center, School of Nutrition and Food Science, Isfahan, Iran #The first two authors equally contributed to this article. *Corresponding Address: P.O.Box: 81746-73461, Hezar Jarib Street, Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran Email: [email protected] Received: 21/Nov/2016, Accepted: 14/Mar/2017 Abstract Objective: For the first time, we used molecular signaling pathway enrichment analysis to determine possible involvement of miR-126 and IRS-1 in neurotrophin pathway. Materials and Methods: In this prospective study, validated and predicted targets (targetome) of miR-126 were collected following searching miRtarbase (http://mirtarbase.mbc.nctu.edu.tw/) and miRWalk 2.0 databases, respectively. Then, approximate expression of miR-126 targeting in Glioma tissue was examined using UniGene database (http://www.ncbi. nlm.nih.gov/unigene). In silico molecular pathway enrichment analysis was carried out by DAVID 6.7 database (http://david.
    [Show full text]
  • Editorials & Perspectives
    EDITORIALS & PERSPECTIVES Dendritic cell, monocyte, B and NK lymphoid deficiency defines the lost lineages of a new GATA-2 dependent myelodysplastic syndrome Venetia Bigley and Matthew Collin Institute of Cellular Medicine, Newcastle University, UK. E-mail: [email protected] doi:10.3324/haematol.2011.048355 (Related Original Article on page 1221) novel immunodeficiency syndrome has recently been International Prognostic Scoring System (IPSS). defined in young adults. Known variously as dendritic It is worth emphasizing at this point that DCML deficiency cell, monocyte, B and NK lymphoid (DCML deficien - patients may have significant risk to their health before addi - A1 2 2 cy), ‘autosomal dominant and sporadic monocytopenia’ or tional cytopenias evolve. Disseminated mycobacterial infec - ‘MonoMAC’ (monocytopenia with Mycobacterium avium com - tion, PAP and carcinoma in situ may all occur prior to the onset plex), 3 it is characterized by a composite mononuclear cell defi - of an obvious myelodysplastic syndrome, underscoring the ciency, atypical mycobacterial and viral infection, and progres - fact that immunodeficiency is a cardinal feature of the disor - sion to myelodysplasia and leukemia. Strikingly, a number of der. In the series of 4 subjects described in 2011, one had mild patients also develop pulmonary alveolar proteinosis (PAP). anemia (10.3 g/dL) and one mild thrombocytopenia Patients typically present in their 3 rd or 4 th decade, although his - (123 ¥10 9/L), yet 2 required hematopoietic stem cell transplan - torical blood counts may show pre-existing monocytopenia tation (one for refractory mycobacterial infection, one for PAP) for ten years or more. A substantial number of patients devel - and a third died of influenza H1N1 prior to transplantation.
    [Show full text]
  • PBX3 and MEIS1 Cooperate in Hematopoietic Cells to Drive Acute
    Published OnlineFirst January 8, 2016; DOI: 10.1158/0008-5472.CAN-15-1566 Cancer Molecular and Cellular Pathobiology Research PBX3 and MEIS1 Cooperate in Hematopoietic Cells to Drive Acute Myeloid Leukemias Characterized by a Core Transcriptome of the MLL-Rearranged Disease Zejuan Li1, Ping Chen1, Rui Su2, Chao Hu1,2,3, Yuanyuan Li1, Abdel G. Elkahloun4, Zhixiang Zuo1,2, Sandeep Gurbuxani5, Stephen Arnovitz1, Hengyou Weng1,2, Yungui Wang1,2,3, Shenglai Li1, Hao Huang1, Mary Beth Neilly1, Gang Greg Wang6, Xi Jiang1,2, Paul P. Liu4, Jie Jin3, and Jianjun Chen1,2 Abstract Overexpression of HOXA/MEIS1/PBX3 homeobox genes is sion profiling of hematopoietic cells demonstrated that PBX3/ the hallmark of mixed lineage leukemia (MLL)-rearranged MEIS1 overexpression, but not HOXA9/MEIS1, HOXA9/PBX3, acute myeloid leukemia (AML). HOXA9 and MEIS1 are con- or HOXA9 overexpression, recapitulated the MLL-fusion–medi- sideredtobethemostcriticaltargetsofMLLfusionsandtheir ated core transcriptome, particularly upregulation of the endog- coexpression rapidly induces AML. MEIS1 and PBX3 are not enous Hoxa genes. Disruption of the binding between MEIS1 individually able to transform cells and were therefore hypoth- andPBX3diminishedPBX3/MEIS1–mediated cell transforma- esized to function as cofactors of HOXA9. However, in this tion and HOX gene upregulation. Collectively, our studies study, we demonstrate that coexpression of PBX3 and MEIS1 strongly implicate the PBX3/MEIS1 interaction as a driver of (PBX3/MEIS1), without ectopic expression of a HOX gene, is cell transformation and leukemogenesis, and suggest that this sufficient for transformation of normal mouse hematopoietic axis may play a critical role in the regulation of the core stem/progenitor cells in vitro.Moreover,PBX3/MEIS1 overex- transcriptional programs activated in MLL-rearranged and pression also caused AML in vivo, with a leukemic latency HOX-overexpressing AML.
    [Show full text]
  • Secondary Pulmonary Alveolar Proteinosis in Hematologic
    review Secondary pulmonary alveolar proteinosis in hematologic malignancies Chakra P Chaulagain a,*, Monika Pilichowska b, Laurence Brinckerhoff c, Maher Tabba d, John K Erban e a Taussig Cancer Institute of Cleveland Clinic, Department of Hematology/Oncology, Cleveland Clinic in Weston, FL, USA, b Department of Pathology, Tufts Medical Center Cancer Center & Tufts University School of Medicine, Boston, MA, USA, c Department of Surgery, Tufts Medical Center Cancer Center & Tufts University School of Medicine, Boston, MA, USA, d Division of Critical Care, Pulmonary and Sleep Medicine, Tufts Medical Center Cancer Center & Tufts University School of Medicine, Boston, MA, USA, e Division of Hematology/Oncology, Tufts Medical Center Cancer Center & Tufts University School of Medicine, Boston, MA, USA * Corresponding author at: Cleveland Clinic Florida, 2950 Cleveland Clinic Blvd., Weston, FL 33331, USA. Tel.: +1 954 659 5840; fax: +1 954 659 5810. Æ [email protected] Æ Received for publication 29 January 2014 Æ Accepted for publication 1 September 2014 Hematol Oncol Stem Cell Ther 2014; 7(4): 127–135 ª 2014 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved. DOI: http://dx.doi.org/10.1016/j.hemonc.2014.09.003 Abstract Pulmonary alveolar proteinosis (PAP), characterized by deposition of intra-alveolar PAS positive protein and lipid rich material, is a rare cause of progressive respiratory failure first described by Rosen et al. in 1958. The intra-alveolar lipoproteinaceous material was subsequently proven to have been derived from pulmonary surfactant in 1980 by Singh et al. Levinson et al. also reported in 1958 the case of 19- year-old female with panmyelosis afflicted with a diffuse pulmonary disease characterized by filling of the alveoli with amorphous material described as ‘‘intra-alveolar coagulum’’.
    [Show full text]
  • EGFL7 Meets Mirna-126: an Angiogenesis Alliance
    - http://vascularcell.com/ REVIEW | OPEN ACCESS EGFL7 meets miRNA-126: an angiogenesis alliance Journal of Angiogenesis Research 2:9 | DOI: 10.1186/2040-2384-2-9 | © Li et al.; licensee Publiverse Online S.R.L. 2010 Received: 21 Apr 2010 | Accepted: 8 Apr 2010 | Published: 8 Apr 2010 Nikolic Iva, Plate Karl-Heinz, Schmidt Mirko HH@ + Contributed equally@ Corresponding author Abstract Blood vessels form de novo through the tightly regulated programs of vasculogenesis and angiogenesis. Both processes are distinct but one of the steps they share is the formation of a central lumen, when groups of cells organized as vascular cords undergo complex changes to achieve a tube-like morphology. Recently, a protein termed epidermal growth factor-like domain 7 (EGFL7) was described as a novel endothelial cell-derived factor involved in the regulation of the spatial arrangement of cells during vascular tube assembly. With its impact on tubulogenesis and vessel shape EGFL7 joined the large family of molecules governing blood vessel formation. Only recently, the molecular mechanisms underlying EGFL7's effects have been started to be elucidated and shaping of the extracellular matrix (ECM) as well as Notch signaling might very well play a role in mediating its biological effects. Further, findings in knock-out animal models suggest miR-126, a miRNA located within the egfl7 gene, has a major role in vessel development by promoting VEGF signaling, angiogenesis and vascular integrity. This review summarizes our current knowledge on EGFL7 and miR-126 and we will discuss the implications of both bioactive molecules for the formation of blood vessels.
    [Show full text]
  • 1700407.Full.Pdf
    AGORA | CORRESPONDENCE Haemodynamically proven pulmonary hypertension in a patient with GATA2 deficiency-associated pulmonary alveolar proteinosis and fibrosis To the Editor: We read with great interest the article by BALLERIE et al. [1], which describes the occurrence of pulmonary alveolar proteinosis and fibrosis in a patient with GATA2 deficiency. Interestingly, our team recently managed a similar case, in which the interstitial lung disease eventually led to pulmonary hypertension (PH). A 41-year-old woman was referred to our tertiary care centre in 2014 for a suspected primary immunodeficiency. Her previous medical history included recurrent upper and lower respiratory tract infections, persisting cytopenias (including monocytopenia, and B-cell and natural killer cell lymphopenias), a disseminated Mycobacterium kansasii infection (in 2002) and a myelodysplastic syndrome (in 2008). She also displayed an interstitial lung disease that was first noted on a chest high-resolution computed tomography (HRCT) in 2002. A lung biopsy performed in 2007 showed histological lesions of pulmonary alveolar proteinosis and paraseptal fibrosis. Over the years, the pulmonary disease slowly progressed to involve the whole lung parenchyma. At the time of referral, chest HRCT displayed diffuse interlobular septal thickening, reticulations and ground-glass opacities of both lungs (figure 1a). The overall picture was compatible with the diagnosis of GATA2 deficiency, which was confirmed by molecular biology in October 2014. At the time of GATA2 deficiency diagnosis, the patient complained of a slowly progressive worsening of her dyspnoea and was staged in New York Heart Association functional class IIa. Physical examination showed no sign of right heart failure (including lower limb oedema).
    [Show full text]
  • GATA2 Deficiency and Related Myeloid Neoplasms
    Seminars in Hematology 54 (2017) 81–86 Contents lists available at ScienceDirect Seminars in Hematology journal homepage: www.elsevier.com/locate/enganabound GATA2 deficiency and related myeloid neoplasms Marcin W. Wlodarskia,b,n, Matthew Collinc, Marshall S. Horwitzd a Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology; Medical Center; Faculty of Medicine, University of Freiburg, Germany b German Cancer Consortium (DKTK), Freiburg, Germany and German Cancer Research Center (DKFZ), Heidelberg, Germany c Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; Northern Centre for Bone Marrow Transplantation, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom d Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA article info abstract Available online 19 May 2017 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 Keywords: maintenance of hematopoietic stem cells. During the past 5 years, germline heterozygous mutations Genetic predisposition in GATA2 were reported in several hundred patients with various phenotypes ranging from mild GATA2 deficiency þ cytopenia to severe immunodeficiency involving B cells, natural killer cells, CD4 cells, monocytes and Familial MDS dendritic cells (MonoMAC/DCML), and myeloid neoplasia. Some patients additionally show
    [Show full text]
  • Highly Variable Clinical Manifestations in a Large Family with a Novel GATA2 Mutation
    Letters to the Editor 2247 interleukin-2 receptor expression and growth of leukemic Sezary cells. Leukemia 8 Chiarle R, Simmons WJ, Cai H, Dhall G, Zamo A, Raz R et al. Stat3 is required for 2001; 15: 787–793. ALK-mediated lymphomagenesis and provides a possible therapeutic target. 7 Ohgami RS, Ohgami JK, Pereira IT, Gitana G, Zehnder JL, Arber DA. Refining the Nat Med 2005; 11: 623–629. diagnosis of T-cell large granular lymphocytic leukemia by combining distinct patterns 9 Jing N, Tweardy DJ. Targeting Stat3 in cancer therapy. Anticancer Drugs 2005; 16: of antigen expression with T-cell clonality studies. Leukemia 2011; 25: 1439–1443. 601–607. Supplementary Information accompanies this paper on the Leukemia website (http://www.nature.com/leu) Highly variable clinical manifestations in a large family with a novel GATA2 mutation Leukemia (2013) 27, 2247–2248; doi:10.1038/leu.2013.105 non-Hodgkin lymphoma of the nasopharynx with rapidly progressive pancytopenia refractory to high-dose methylprednisolone and rituximab. The lymphoma was immunophenotypically CD3 and CD45 positive but CD4, CD8, CD20, CD30 and CD79a negative Recently, germline mutations in GATA2 have been described in and was classified as peripheral T-cell NHL, not otherwise specified. familial myelodysplastic syndrome/acute myeloid leukemia (MDS/ Bone marrow histology did not show marrow involvement of the AML) and in apparently related clinical conditions, designated lymphoma at the time of pancytopenia. DCML (dendritic cell-, mono- and lymphocytopenia), MonoMac The paternal grandmother of the index patient died at the age (monocytopenia and Mycobacterium avium complex infections) of 74 from AML.
    [Show full text]