Descripción del proyecto
Estudio de la interacción de la leucemia con su microentorno
La leucemia mieloide aguda (LMA), un cáncer de la sangre y la médula ósea, es el tipo más frecuente de leucemia aguda en adultos. Si las células madre leucémicas no se erradican correctamente, su autorrenovación ilimitada conduce a la recaída. Estudios recientes sugieren que las células estromales e inmunitarias de la médula ósea desempeñan un papel importante en la LMA. Sobre la base de los datos que sugieren que la remodelación del microentorno (nicho) por parte de la LMA favorece su supervivencia y suprime la formación de células sanas, el proyecto epiNicheAML, financiado con fondos europeos, utilizará un enfoque nuevo. Investigar la relación entre el nicho estromal intrínseco de las células madre leucémicas y los mecanismos con mediación inmunitaria, en lugar de estudiar cada uno de ellos por separado, podría señalar nuevos tratamientos centrados en restablecer un nicho sano para una inmunidad sana en lugar de erradicar todas las células madre leucémicas.
Objetivo
The bone marrow is one of the most dynamic adult stem cell niches containing hematopoietic stem cells and non-hematopoietic mesenchymal stem and stromal cells, which make up the bone marrow niche. The niche regulates the immune system and constitutes a major determinant of chemoresistance in hematological malignancies, including acute myeloid leukemia (AML). Identifying the mechanisms by which AML interacts with its niche will open novel therapeutic avenues.
AML is driven and maintained by leukemic stem cells (LSCs), and failure to eradicate them will result in relapsing of the disease. Yet, despite decades of research on LSCs, none of the therapies aiming at eradicating them reached clinical practice. Recent studies suggest an important role for bone marrow stromal and immune cells in driving AML. Together with our preliminary data, that show LSCs-induced upregulation of metastasis-related genes in stromal cells, this leads to the hypothesis that AML remodels its niche in ways that favours its survival and represses healthy hematopoiesis.
Most studies in AML focus on LSC-intrinsic, stromal niche, or immune mediated mechanisms separately. Thus, we currently lack a comprehensive view of the complexity of the human bone marrow and its interaction with AML. To close these gaps, we propose an ambitious experimental design including multi-modal single cell sequencing of an AML cohort followed by innovative computational approaches integrating these data into predictive cell-type specific models - to generate mechanistic hypotheses about AML-niche interactions that we then test using patient-derived xenograft and in vitro culture models. Our ambitious project will provide fundamental insights into stem cell-niche interactions and may lead to a paradigm-shift in treating hematological malignancies - away from eradicating malignant cells towards reconstituting a healthy niche that generates a healthy immune environment.
Ámbito científico
- medical and health sciencesbasic medicineimmunology
- medical and health sciencesmedical biotechnologycells technologiesstem cells
- natural sciencescomputer and information sciencescomputational science
- medical and health sciencesbasic medicinepathology
- medical and health sciencesclinical medicineoncologyleukemia
Programa(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régimen de financiación
HORIZON-AG - HORIZON Action Grant Budget-BasedInstitución de acogida
69117 Heidelberg
Alemania