About our research group/lab
As head of the transplantation laboratory, we have a specific interest in understanding HSC biology and transplantation. Furthermore we study inherited defects in HSCs. These defects cause bone marrow failure, marked by severe cytopenias, and predispose to the development of acute myeloid leukemia (AML). A prime example of these leukemia predisposition syndromes is GATA2 deficiency syndrome, caused by germline mutations in GATA2. These patients often have defects in monocytes, dendritic cells, T cells, B cells and neutrophils. Furthermore, they have an 80% change to develop myeloid leukemia before the age of 40. The variety between the types of mutations in GATA2 is extreme, from amino acid substitutions in the protein to frameshift truncating mutations and mutations in regulatory regions of GATA2. Many of these mutations are variants of unknown significance (VUS). Furthermore, phenotypes vary greatly between patients, hampering diagnostics and genetic counselling. We want to understand why defects in HSCs cause leukemic transformation, why these mutations cause such different defects in lineage differentiation and find ways to better predict pathogenicity of VUS.
In my lab we have built various models (zebrafish, mouse and human cell models) to investigate HSC biology and the different aspects of disease pathogenicity of GATA2 deficiency syndrome. We have identified several roles for GATA2 in hematopoiesis where Gata2 is required for the generation of HSCs and for their maintenance and that Gata2 regulates HSPC generation through gfi1b. The zebrafish model recapitulates several disease characteristics, like monocytopenia and B cell differentiation defects in homozygous animals. Furthermore we uncovered that gata2b+/- zebrafish show dysplasia of the kidney marrow (bone marrow orthologue) and that epigenetic changes in the gata2b locus result in normalization of gata2b transcript levels in HSPCs, but thereby deregulate the locus in more differentiated cells. Furthermore, we uncovered in mouse models of Gata2 deficiency that malignant transformation is always preceded by bone marrow failure and that GATA2 is required for proper HSC proliferation, potentially contributing to malignant transformation.
HSC biology and transplantation.
In this research line we want to explore other applications of HSC transplantation. We investigate the effects of HSCs expansion and the effects HSC expansion has on differentiation into different lineages. Furthermore we try to refine current transplantation related procedures like stem cell measurements and harvest from peripheral blood by characterizing the different CD34 progenitor populations and their specific function in autologous transplantation.
The function of various zinc finger missense mutations in leukemic transformation (collaboration with the Delwel lab).
Missense mutations in germline patients mostly occur in zinc finger (ZF) 2, whereas missense mutations in GATA2 in de novo AML occur mostly in ZF1. Therefore, we hypothesize that missense mutations in GATA2 result in changes of the transcriptional complex and/or changes in DNA binding sites regulating expression and that ZF1 and ZF2 have different functions. We investigate this in vivo in the zebrafish system and in vitro in cell models and primary cells. The zebrafish models that we have generated for this are now also used to investigate VUS pathogenicity.
Proliferation defects in GATA2 deficient cells.
We investigate why GATA2 deficient cells have increased DNA damage and chromosomal aberrations. We investigate this using high resolution imaging technologies in cell models.
Variations in onset of immune defects and their role in malignant transformation in GATA2 haploinsufficiency.
Patients with GATA2 mutations have a great variety in type and onset of cytopenias. We investigate if the epigenetic changes observed after heterozygous GATA2 mutations are the cause of the immune differences between patients carrying the same GATA2 mutation. To explore the defects in lineage committed cells and their potential role in leukemic transformation we want to further explore the interaction of HSPCs and the (immune)microenvironment, using bone marrow organoids from (patient derived) iPSCs.
Within the Erasmus MC
- Ruud Delwel (Hematology)
- Jeroen de Jonge (Internal Medicine) en Sebastiaan Heidt
- Peter te Boekhorst & Ruben van Dijck (Hematology)
Collaboration outside the Erasmus MC
- Rui Monteiro (Birmingham) - https://www.birmingham.ac.uk/staff/profiles/cancer-genomic/monteiro-rui
- Miriam Erlacher (Ulm) - https://www.uniklinik-ulm.de/kinder-und-jugendmedizin/forschung-research/prof-erlacher-group.html
- Francesco Saettini (Milan) - https://www.researchgate.net/profile/Francesco-Saettini-2
- Marlene Pasquet (Toulouse) - https://www.crct-inserm.fr/annuaire/marlene-pasquet/
- Trudy Straetemans (UMCU – DARE-NL) - www.dare-nl.nl
- Martie Verschuren (Avans hogeschool)
Pharma-NL/ZonMW – Toekomst gerichte training voor cel en gen-therapie professionals (collaboration with Avans hogeschool)
ZonMW-Open - HSCs as avalanche fence (collaboration Jeroen de Jonge and Marcel Otten (TU Delft))
KWF – Deconstructing the molecular mechanism of mutant-GATA2 driven leukemogenesis (collaboration Delwel group)
KWF infrastructure grant – DARE-NL (collaboration all national UMCs, PMS and Sanquin)
European Joint Programme on Rare diseases - 3D-GATA2 (European consortium)
