Project description
Targeting leukemic stem cells
Acute myeloid leukemia (AML) remains a devastating disease with less than 30 % of patients surviving five years after diagnosis. The resistance of AML is driven by small subpopulations of leukemic stem cells (LSCs), which survive chemotherapy and elude immune surveillance. LSCs have growth advantages induced by oncogenic mutations but are in many ways similar to healthy hematopoietic stem cells (HSCs). LSCs are located in protective bone marrow niches promoting stemness and therapy resistance and modify these to displace HSCs for their own expansion. The EU-funded Hemstem project explores strategies to target LSCs based on the knowledge of the complex interactions between LSCs and HSCs and provides a rationale for novel treatments.
Objective
Human acute myeloid leukemia (AML) remains a devastating disease with less than 30% of patients surviving five years after diagnosis. Despite decades of research and detailed mo-lecular insights provided by mutational profiling, curative treatment still requires high-intensity chemotherapy and the crude approach of allogeneic stem cell transplantation – an effective, yet non-specific immunotherapy that is costly to the patient because of its severe side effects. One reason why the wealth of molecular and experimental knowledge has so far been unable to revolutionize treatments is the fact that AML is driven by small subpopulations of so-called leukemic stem cells (LSCs), which survive chemotherapy and immune surveillance. LSCs have growth advantages induced by oncogenic mutations, but are in many ways similar to healthy hematopoietic stem cells (HSCs). This similarity makes it difficult to target LSCs without simultaneously eradicating HSCs and healthy hematopoiesis derived from these cells. Like HSCs, LSCs home to protective bone marrow (BM) niches promoting stemness and therapy resistance and modify them to displace HSCs and promote their own expansion. This proposal explores strategies to target LSCs based on understanding these interactions. In Aim 1 we investigate how WNT signaling, an evolutionary conserved pathway governing stem cell self-renewal, regulates interactions between leukemic and healthy hematopoietic (stem) cells. In Aim 2, we propose to inhibit the in vivo expansion of LSCs by enhancing self-renewal and niche affinity in their natural competitors, the healthy stem cells with inborn BM homing ability. Aim 3 uses zebrafish to visualize LSC-HSC interactions and screens for molecules supporting healthy instead of (pre-) malignant hematopoiesis. Our studies will im-prove the knowledge on the complex interactions between LSCs and HSCs and provide a rationale for novel treatments that might lead to a paradigm-shift in the clinical management of AML.
Fields of science
- medical and health sciencesmedical biotechnologycells technologiesstem cells
- natural sciencesbiological sciencesgeneticsmutation
- medical and health sciencesbasic medicineimmunologyimmunotherapy
- medical and health sciencesclinical medicinetransplantation
- medical and health sciencesclinical medicineoncologyleukemia
Keywords
Programme(s)
Funding Scheme
ERC-COG - Consolidator GrantHost institution
72074 Tuebingen
Germany