Hematological phenotypes in GATA2 deficiency syndrome arise from aging maladaptation to proliferation and somatic events.
Juncal Fernandez-Orth, Cansu Koyunlar, Julia Miriam Weiss, Emanuele Gioacchino, Hans W J de Looper, Geoffroy Andrieux, Mariette Ter Borg, Joke Zink, Irene Gonzalez Menendez, Remco Hoogenboezem, Baris Ismail Yigit, Kirsten Gussinklo, Roger Mulet-Lazaro, Charlotte Wantzen, Sophie Pfeiffer, Christian Molnar, Eric Bindels, Sheila Bohler, Mathijs Arnoud Sanders, Leticia Quintanilla-Martinez, Marcin W Wlodarski, Melanie Boerries, Ivo P Touw, Charlotte Niemeyer, Miriam Erlacher, Emma de Pater
Author Information
Juncal Fernandez-Orth: University Hospital Ulm, Ulm, Germany.
Hans W J de Looper: Erasmus MC, Rotterdam, Netherlands.
Geoffroy Andrieux: Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany, Freiburg, Germany. ORCID
Mariette Ter Borg: Erasmus University Medical Center, Rotterdam, Netherlands.
Joke Zink: Erasmus MC, Rotterdam, Netherlands.
Irene Gonzalez Menendez: University of Tuebingen, T��bingen, Germany.
Roger Mulet-Lazaro: Erasmus MC Cancer Institute, Rotterdam, Netherlands. ORCID
Charlotte Wantzen: University Medical Center Freiburg, Division of Pediatric Hematology and Oncoogy, Freiburg, Germany.
Sophie Pfeiffer: ZTZ, University Medical Center Freiburg, Freiburg, Germany.
Christian Molnar: University Medical Center Freiburg, Division of Pediatric Hematology and Oncology, Freiburg, Germany.
Eric Bindels: ErasmusMC, rottterdam, Netherlands.
Sheila Bohler: University Medical Center Freiburg, Division of Pediatric Hematology and Oncoogy, Freiburg, Germany. ORCID
Mathijs Arnoud Sanders: Erasmus University Medical Center, Rotterdam, Netherlands. ORCID
Leticia Quintanilla-Martinez: University Hospital Tuebingen, Tuebingen, Germany. ORCID
Marcin W Wlodarski: St. Jude Children Research Hospital, Memphis, Tennessee, United States. ORCID
Melanie Boerries: Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University ofer Freiburg, Freiburg, Germany. ORCID
Ivo P Touw: Erasmus MC, Rotterdam, Netherlands.
Charlotte Niemeyer: University Medical Center Freiburg, Division of Pediatric Hematology and Oncoogy, Freiburg, Germany.
Miriam Erlacher: Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany. ORCID
Emma de Pater: Erasmus MC, rotterdam, Netherlands.
The GATA2 transcription factor is a pivotal regulator of hematopoiesis. Disruptions in the GATA2 gene drive severe hematologic abnormalities and are associated with an increased risk of myelodysplastic syndromes and acute myeloid leukemia; however, the mechanisms underlying the pathophysiology of GATA2 deficiency remain still unclear. We developed two different mouse models that are based on serial and limiting donor cell transplantation of (aged) GATA2 haploinsufficient cells and mirror the symptoms of GATA2 deficiency. Similar to what has been observed in patients, our models show that GATA2 haploinsufficiency leads to B lymphopenia, monocytopenia, lethal bone marrow failure (BMF), myelodysplasia and lymphoblastic leukemia. Leukemia arises exclusively as a result of BMF, driven by somatic aberrations and accompanied by increased Myc target expression and genomic instability. These findings were confirmed in human GATA2+/- K562 cell lines showing defects in cytokinesis and are in line with the fact that monosomy 7 and trisomy 8 are frequent events in patients with MDS.
