MYCHSC · Dissecting the role of Myc and Jun in hematopoietic stem cell self-renewal and cancer formation
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2007-04-01 → 2009-03-31
- EU contribution
- €186,289
- Participants
- 2
- Scheme
- IIF
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Results in brief
Final Activity Report Summary - MYCHSC (Dissecting the role of Myc and Jun in hematopoietic stem cell self-renewal and cancer formation)
In order to identify the role of the 'Tif1?' gene in blood (hematopoietic) development, we removed the activity of this gene in hematopoietic precursors in the early mouse embryo and analysed the subsequent blood phenotype. The first identifiable blood defect observed upon complete absence of Tif1? activity was a reduced number of hematopoietic stem cell (HSC) emergence from within the embryo. Prominent cell death of hematopoietic progenitors and erythroid (red blood cell) precursors was observed in the following 48hrs of development, ultimately leading to complete loss of foetal liver and placental HSC activity. Loss of Tif1? activity in blood precursor cells is incompatible with life and embryos die due to a lack of functional blood cells. Collectively, our data demonstrate that Tif1? is crucial for the generation, survival and functional activity of definitive HSCs.
Data: CORDIS, © European Union
Project objective
All stem cell populations are controlled by a number of intrinsic and external regulatory mechanisms that function in maintaining balance between stem cell self-renewal and commitment to differentiation.Recent evidence also suggests that some cancers are controlled by a small population of tumour cells that exhibit stem cell like qualities (referred to as cancer stem cells) lending to the hypothesis that cancer is a disease of uncontrolled stem cell self-renewal. This proposal aims to elucidate how the transcription factors c-Myc, N-Myc and c-Jun interact with each other to control haematopoietic stem cell (HSC) fate.We will induce the conditional deletion and over-expression of these genes in mouse adult HSCs and single/double mutant HSCs will be subsequently injected into lethally irradiated mice, quantified by limited dilution assays and the effects on the stem and progenitor cell pool and each of the haematopoietic lineages assessed by cell cycle analysis and FACS.Particular focus will be placed on identifying how these proteins govern the molecular interaction between HSCs and their micro-environment (stem cell niche). An in depth knowledge of these mechanisms will be crucial in the development of conditions suitable for the in vitro expansion of adult HSC populations for clinical applications.This project also aims to elucidate the role of the c-Myconcogene in an AP-1 driven chronic myeloid leukaemia (CML) model. We will over-express the c-Myconcogene in a JunB-derived CML mouse model to address the r ole of c-Myc in regulating the malignant expansion of leukaemic stem cells.These data will provide insight into how signalling pathways governing normal stem cell homeostasis regulate tumour formation, thus allowing the development of novel treatments for the elimination of cancer cells.
Original text from CORDIS.
Participants
- ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE · LAUSANNECoordinatorSwitzerland
- SWISS INSTITUTE FOR EXPERIMENTAL CANCER RESEARCH · EPALINGESCity levelSwitzerland
Links
Data: CORDIS, © European Union