Hematological phenotypes in GATA2 deficiency syndrome arise from aging, maladaptation to proliferation, and somatic events
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.
Authors
- Emanuele Gioacchino (ORCID: https://orcid.org/0000-0002-2787-6286)
- Kirsten J. Gussinklo
- Cansu Koyunlar (ORCID: https://orcid.org/0000-0002-9006-1135)
- Melanie Boerries (ORCID: https://orcid.org/0000-0002-3670-0602)
- Miriam Erlacher (ORCID: https://orcid.org/0000-0002-7261-1447)
- Julia Miriam Weiss
- Marcin W. Włodarski (ORCID: https://orcid.org/0000-0001-6638-9643)
- Leticia Quintanilla-Martı́nez (ORCID: https://orcid.org/0000-0001-7156-5365)
- Joke Zink
- Remco M. Hoogenboezem (ORCID: https://orcid.org/0000-0002-1719-6455)
- Eric Bindels
- Emma de Pater (ORCID: https://orcid.org/0000-0002-7195-6769)
- Geoffroy Andrieux (ORCID: https://orcid.org/0000-0002-5389-9481)
- Hans W. J. de Looper
- Irene González-Menéndez (ORCID: https://orcid.org/0000-0003-3608-4704)
- Mathijs A. Sanders (ORCID: https://orcid.org/0000-0002-8575-9213)
- Christian Molnár (ORCID: https://orcid.org/0000-0002-7852-9233)
- Roger Mulet‐Lazaro (ORCID: https://orcid.org/0000-0003-0298-7948)
- Sheila Bohler (ORCID: https://orcid.org/0000-0001-8860-9424)
- Juncal Fernández‐Orth (ORCID: https://orcid.org/0000-0002-6870-6830)
- Charlotte Wantzen
- Charlotte M. Niemeyer (ORCID: https://orcid.org/0000-0003-3856-7937)
- Sophie Pfeiffer (ORCID: https://orcid.org/0009-0005-3069-0940)
- Baris Yigit
- Ivo P. Touw
- Mariëtte ter Borg
Institutions
- St. Jude Children's Research Hospital (US)
- University of Freiburg (DE)
- Universität Ulm (DE)
- University Medical Center Freiburg (DE)
- Erasmus MC (NL)
- Erasmus MC Cancer Institute (NL)
- Becton Dickinson (Netherlands) (NL)
- University Hospital Ulm (DE)
- University of Tübingen (DE)
- Erasmus University Rotterdam (NL)
Publication Details
- Journal
- Blood Advances
- Published
- 2025-03-26
- DOI
- https://doi.org/10.1182/bloodadvances.2024015106
- Citations
- 3
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 5.31