Objective
Human leukaemias are associated with identified genetic alterations including recurrent chromosomal translocations which lead to the synthesis of novel fusion proteins or to the ectopic or enhanced expression of normal proteins and deletion and point mutations which result in loss of function of tumour suppressor genes. Although considerable progress has been made in the identification of genes associated with specific leukaemias and the way their expression is altered, much less is know on how single genetic alterations contribute to leukaemic development and how dominant oncogenes and recessive tumour suppressor genes cooperate to generate the full leukaemic phenotype. We propose to use and further develop new cellular models to analyse how oncoproteins and tumour suppressors which are known to be involved in human leukaemias alter the proliferation, survival and differentiation control of primary hematopoietic progenitors in tissue culture. Fusion proteins involved in preleukaemic states like myeloid dysplastic syndromes (MDS), in chronic myelogenous leukaemia (CML) and in acute leukaemias of both the myeloid (AML) and lymphoid (ALL) lineage's will be considered. Specifically, we will analyse the properties of CMML-associated Tel-PDGFRbeta, of CML-associated BCR-ABL and of several oncoproteins associated with AML including PML-RARalpha, DEK-CAN, TLS-ERG as well as AML1 and MLL fusion proteins.
Very few genetics alterations are known to be implicated in MDS. A major effort will be put in the identification of novel genetic lesions specific to MDS and in the study of the activity of the corresponding genes in hematopoietic progenitors.
The cellular models we propose to use are also ideally suited to investigate how known tumour suppressor like p53 or candidate suppressor genes like ERF co-operate with oncoproteins to deregulate the growth and differentiation control of hematopoietic progenitors.
To validate the results obtaind in tissue culture, we will develop a complementary approach in which ES cells will be genetically modified to express specific human oncoproteins as combinations thereof. These cells will be used to create chimeric animals in which leukaemia development can be monitored.
Description of the phenotypes associated with the expression of single oncoproteins and tumour suppressors or combinations thereof in primary progenitors paves the way to develop a screening assay for pharmacological compounds interfering with the function of these proteins.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences biochemistry biomolecules proteins
- natural sciences biological sciences genetics mutation
- medical and health sciences clinical medicine oncology leukemia
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Coordinator
91405 ORSAY
France
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