We obtain detailed knowledge on (molecular) mechanisms that determine hematopoietic stem cell self-renewal and differentiation, with the ultimate goal to deepen our insights in the development of human leukemias.
We have a specific interest in dissecting the clonal heterogeneity of leukemias and recently developed tools that allow us to identify and prospectively isolate genetically distinct clones within individual patients. A similar level of heterogeneity is seen within the tumor microenvironment in the bone marrow of patients, and we aim to functionally characterize stromal cells and various innate and adaptive immune cells in the context of developing leukemic clones.
We perform gene-function analyses in human hematopoietic stem and progenitor cells isolated from cord blood and bone marrow utilizing various strategies including optimized CRISPR/Cas9 approaches. We have a longstanding expertise in using molecular approaches (transcriptome, proteome, metabolome and epigenome) to further understand processes such as hematopoietic differentiation, proliferation, apoptosis and self-renewal.
We make use of humanized niche xenograft models in which 3D scaffolds coated with human stromal cells are implanted in mice in order to mimic that situation in leukemia patients as closely as possible. Furthermore, we directly collaborate with the clinical and diagnostic departments at the UMCG and have banked large longitudinal series of leukemic patient material available for our research. We anticipate that our studies will lead to a more rational approach in the clinic of this highly malignant disorder.
Our research lines include:
- Mechanisms involved in HSC self-renewal and hematopoietic lineage commitment
- Interactions between HSCs and their microenvironment, including the impact on the metabolome
- Molecular mechanisms underlying the development of Acute Myeloid Leukemia
- Role of epigenetics in normal and leukemic stem cells
- Deciphering clonal heterogeneity in AML
- Analyses of the immune microenvironment including the role of macrophages and T cells on AML
- Development of anti-Tag CAR-T cells for subclone-specific targeting in AML
- Analysis of the physical properties of leukemic stem cells - see also the 'Physics of Cancer' consortium