TY - JOUR
T1 - Hematological phenotypes in GATA2 deficiency syndrome arise from aging, maladaptation to proliferation, and somatic events
AU - Fernandez-Orth, Juncal
AU - Koyunlar, Cansu
AU - Weiss, Julia M.
AU - Gioacchino, Emanuele
AU - de Looper, Hans
AU - Andrieux, Geoffroy
AU - Borg, Mariëtte ter
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
N1 - Publisher Copyright:
© 2025 American Society of Hematology.
PY - 2025/6/10
Y1 - 2025/6/10
N2 - 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.
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.
UR - https://www.scopus.com/pages/publications/105007208442
U2 - 10.1182/bloodadvances.2024015106
DO - 10.1182/bloodadvances.2024015106
M3 - Article
C2 - 40138552
AN - SCOPUS:105007208442
SN - 2473-9529
VL - 9
SP - 2794
EP - 2807
JO - Blood Advances
JF - Blood Advances
IS - 11
ER -