De Pater lab

The de Pater lab studies the role of the transcription factor GATA2 in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).

The transcription factor GATA2 is recurrently mutated in AML. Furthermore, the most common germline defect in childhood MDS/AML is a mutation in GATA2. The mutational spectrum of GATA2 in these patients is very diverse, as are the phenotypes of the patients.

Some patients have severe hematological deficiencies, while others only have a predisposition for MDS/AML. The reason for this is unknown. These patients have innate mutations in GATA2, which means that these mutations are also present during embryonic development of the hematopoietic system. Innate mutations in Gata2 in mouse and zebrafish result in a severe reduction in the number of HSCs that are generated in the embryo.

A novel zebrafish model for GATA2 haploinsufficiency mimics patient characteristics like monocytopenia and dysplasia. The de Pater group is currently investigating the mechanism of malignant transformation in this model and the embryonic role of GATA2 to the contribution of leukemia predisposition. Furthermore, the types of mutations found in de novo AML and in patients with a germline predisposition for MDS/AML are different and how these mutations result in leukemogenesis and deregulate transcription are subject of active investigation.

The role of GATA2 zinc finger mutations in leukemogenesis

Mutations in GATA2 occur both de novo - in sporadic AML and in the germline - resulting in a predisposition for AML, but de novo mutations usually occur in the first zinc finger of GATA2 and in germline GATA2 mutations they occur most frequently in the second zinc finger, indicating a functional difference between the two. We would like to find out what that difference is.

The role of GATA2 haploinsufficiency in lineage differentiation

Germline GATA2 mutations can also cause frameshift truncating mutation, resulting in the deletion of one allele. These patients often present with defects in normal blood formation and we want to understand how GATA2 haploinsufficiency controls this.

Regulation of GATA2

GATA2 expression is tightly regulated and can account for the onset of GATA2 deficiency syndrome leading to several and diverse phenotypes like cytopenias, lymphedema and onset of malignancy. In zebrafish there are two isoforms, but each is expressed in different issues. We want to identify the differences in the regulatory elements that cause these expression patterns, elucidating which factors are important for the differences in GATA2 expression in various cell types.

Leukemic transformation in GATA2 deficiency syndrome

Mutations in GATA2 predispose to leukemia. We have generated several animal and cell models that mimic this and we want to identify the molecular mechanism that drives the leukemic transformation in these models.

Within the Erasmus MC

• Delwel lab
• Sanders lab

• De Jonge/Luimes - Internal medicine

• Erkeland - Immunology

• Pijnappels - Clinical genetics

Collaboration outside the Erasmus MC

• Erlacher Lab - Freiburg/Ulm, Germany
• Pasquet Lab - Toulouse, France
• Monteiro Lab - Birmingham, UK

• Jul 2023: KWF project grant
• Sept 2022: EHA advanced research fellowship
• Sept 2022: KWF infrastructure grant DARE-NL
• Dec 2021: Erasmus MC foundation
• Jun 2017: KWF junior fellowship, Bas Mulder award
• May 2015: EHA non clinical junior research fellowship