Descrizione del progetto
Cellule staminali che intervengono sulla leucemia
La leucemia mieloide acuta (LMA) è tuttora una malattia devastante, con una percentuale inferiore al 30 % di pazienti che sopravvivono a cinque anni dalla diagnosi. La resistenza della LMA è dovuta a piccole sottopopolazioni di cellule staminali leucemiche (LSC), che sopravvivono alla chemioterapia ed eludono la sorveglianza immunitaria. Le LSC presentano vantaggi di crescita indotti dalle mutazioni oncogene, ma sono per molti aspetti simili alle cellule staminali ematopoietiche (HSC). Le LSC risiedono in nicchie midollari protettive e, favorendo la resistenza alla staminalità e alla terapia, le modificano per rimuovere le HSC ai fini della propria espansione. Il progetto Hemstem, finanziato dall’UE, esplora le strategie da rivolgere alle LSC in base alle conoscenze sulle complesse interazioni tra LSC e HSC e fornisce un razionale per nuovi trattamenti.
Obiettivo
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.
Campo scientifico
- 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
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-COG - Consolidator GrantIstituzione ospitante
72074 Tuebingen
Germania