Multi-scale, single-cell systems biology of leukemia stem cells in pathogenesis

Acute Myeloid Leukemia (AML) is an aggressive hematologic malignancy characterized by the accumulation of clonal myeloid progenitor cells arrested in their ability to differentiate into mature blood cells. Despite classic chemotherapy regimens typically lead to remission the relapse rates are still very high, resulting in poor 5-year overall survival rates. Relapse and refractoriness are caused by a small population of leukemic stem cells (LSCs) capable of initiating and sustaining the disease. LSCs harbor a series of traits that likely render them less susceptible to conventional therapies (self-renewal, quiescence, apoptosis resistance and increased drug efflux activity), aimed at the bulk proliferative disease. In addition, a specific stromal and immune niche likely contributes to the regulation of LSC maintenance.  

This project aims to develop and apply novel multi-scale, multi-omics and spatially resolved single-cell approaches to study genetic, metabolic and molecular properties of LSCs from AML samples with normal karyotype (NPM1wt). Besides, it will pursue the mapping of the LSC microenvironment within the bone marrow niche; thereby, contributing to a systems-oriented and personalized understanding of leukemogenesis, the identification of molecular biomarkers and metabolic processes specific to LSCs as well as the evaluation of their therapeutic potential