Molecular mechanisms involved self-renewal of leukemic stem cells from AML patients

hematopoiesis leukemic stem cells self-renewal human hematopoietic stem cells

prof. dr. J.J. Schuringa
prof.dr. E. Vellenga

Type of project:
Stage Wetenschap / Research project

Nature of the research:
Stage Wetenschap / Research project

Fields of study:
oncology haematology

Background / introduction
Acute myeloid leukemia (AML) consists of a heterogeneous population of malignant cells that appears to be hierarchically structured, just as the normal hematopoietic system. Within this heterogeneous population of AML cells only a limited number of primitive cells can self-renew, termed leukemic stem cells. These leukemic stem cells can engraft NOD-SCID/NSG mice, are relatively insensitive to chemotherapy, and are most likely the main cause of relapse of disease. In order to improve treatment strategies, we need to obtain more insight into the biology of these leukemic stem cells
Research question / problem definition
We recently finished a study in which the transcriptomes of primary leukemic stem cell-enriched populations were compared to transcriptomes of their non-self-renewing daughter cells (n=50). Data were also compared to a large cohort of stem cells isolated from normal bone marrow. These studies have led to the identification of leukemic stem cell gene expression signatures that predict prognosis of patients. Some of these genes are involved in the regulation of glucose metabolism. We would now like to characterize how these genes contribute to self-renewal and transformation potential of leukemic stem cells.
-Genetically target some of the identified genes using a lentiviral approach, both in normal human stem cells as well as in leukemic stem cells isolated from primary patient samples.
-Determine the cellbiological consequences of targeting these genes (self-renewal, differentiation, survival)
-Determine whether targeting these genes, in combination with standard chemotherapy, is beneficial in eradicating leukemic stem cells.
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