TY  - JOUR
AU  - Fernandez-Orth, Juncal
AU  - Koyunlar, Cansu
AU  - Weiss, Julia M
AU  - Gioacchino, Emanuele
AU  - de Looper, Hans
AU  - Andrieux, Geoffroy
AU  - Ter Borg, Mariëtte
AU  - Zink, Joke
AU  - Gonzalez-Menendez, Irene
AU  - Hoogenboezem, Remco
AU  - Yigit, Baris
AU  - Gussinklo, Kirsten J
AU  - Mulet-Lazaro, Roger
AU  - Wantzen, Charlotte
AU  - Pfeiffer, Sophie
AU  - Molnar, Christian
AU  - Bindels, Eric
AU  - Bohler, Sheila
AU  - Sanders, Mathijs
AU  - Quintanilla-Martinez, Leticia
AU  - Wlodarski, Marcin
AU  - Boerries, Melanie
AU  - Touw, Ivo P
AU  - Niemeyer, Charlotte
AU  - Erlacher, Miriam
AU  - de Pater, Emma
TI  - Hematological phenotypes in GATA2 deficiency syndrome arise from aging, maladaptation to proliferation, and somatic events.
JO  - Blood advances
VL  - 9
IS  - 11
SN  - 2473-9529
CY  - Washington, DC
PB  - American Society of Hematology
M1  - DKFZ-2025-01140
SP  - 2794 - 2807
PY  - 2025
AB  - 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 still remain unclear. We developed 2 different mouse models that are based on serial and limiting donor-cell transplantation of (14-15 months) GATA2 haploinsufficient cells and mirror the symptoms of GATA2 deficiency. Similar to what has been observed in patients, our models showed that GATA2 haploinsufficiency leads to B lymphopenia, monocytopenia, lethal bone marrow failure (BMF), myelodysplasia, and lymphoblastic leukemia. Leukemia arises exclusively because 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 myelodysplastic syndrome.
KW  - Animals
KW  - Mice
KW  - Humans
KW  - GATA2 Transcription Factor: genetics
KW  - GATA2 Transcription Factor: deficiency
KW  - GATA2 Deficiency: genetics
KW  - GATA2 Deficiency: pathology
KW  - Phenotype
KW  - Cell Proliferation
KW  - Myelodysplastic Syndromes: genetics
KW  - Myelodysplastic Syndromes: pathology
KW  - Haploinsufficiency
KW  - Aging: genetics
KW  - Disease Models, Animal
KW  - K562 Cells
KW  - GATA2 Transcription Factor (NLM Chemicals)
KW  - GATA2 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40138552
DO  - DOI:10.1182/bloodadvances.2024015106
UR  - https://inrepo02.dkfz.de/record/301756
ER  -