Identification of molecular mechanisms governing normal and malignant human blood stem cell self-renewal

• Applicant: Dr. Kerstin Kaufmann
• Subject Area: Hematology, Oncology ; Cell Biology
• Term: from 2015 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 290575071

A growing body of evidence indicates that leukemia stem cells and recently identified preleukemic blood stem cells can survive standard chemotherapy and initiate disease relapse in acute myeloid leukemia. In contrast to normal blood stem cells, leukemia stem cells have lost the ability to develop into mature blood cells but retain the ability to self-renew (generate a daughter cell with identical functional properties) and differentiate (produce progeny with varied, dissimilar properties). Further insights into normal and malignant blood cell development are necessary in order to expand the therapeutic options for patients suffering from this life-threatening disease and to prevent relapse. This study aims to identify novel stem cell programs through the functional evaluation of candidate genes categorized as more active in normal and malignant human blood stem cells in comparison to their progeny. Since both stem cell populations share functional and molecular characteristics of stemness, the lack of these programs in their immediate committed offspring will facilitate the extraction of self-renewal determinants. In contrast to previous studies, this selection is based on data generated from functionally validated stem and progenitor cell populations. To assess whether expression of these genes is functionally relevant for stem cell activity requires in vivo assays transplanting gene-modified human blood stem and progenitor cells into immunocompromised mice that are able to generate a human graft. Therefore, an advanced, competitive in vivo gain-of-function screen will be employed to ascertain genes and pathways that are critical to stem cell self-renewal. Subsequently, it will be assessed if the self-renewal programs uncovered play similar or distinct roles in normal blood cell development versus leukemia and whether they are of clinical relevance. Deciphering the detailed mode of action of validated self-renewal genes and pathways is expected to provide novel pharmacological targets for future clinical applications in leukemia treatment and blood stem cell based therapies.

• DFG Programme: Research Fellowships
• International Connection: Canada
• Host: John Dick, Ph.D.