Description du projet
Les mécanismes essentiels communs aux différents cas de translocation dans la leucémie myéloïde aiguë
La leucémie myéloïde aiguë (LMA) est un cancer du sang. Le taux de survie à cette pathologie est d’autant plus faible que les décisions cliniques se heurtent à sa complexité génétique, ce qui a un impact sur les options thérapeutiques personnalisées. Les aberrations chromosomiques créent des protéines de fusion qui agissent comme de puissants oncogènes. Les réarrangements chromosomiques sont inclus dans les familles de translocation multipartenaires (TMP) avec un gène spécifique fusionné à une variété de récepteurs. Le projet ONCOMECHAML, financé par le CER, vise à identifier les composants communs critiques de l’oncogenèse dans les familles de TMP de la LMA, en procédant à une analyse comparative de 20 protéines de fusion différentes. L’objectif est d’identifier les protéines partenaires de la protéine de fusion et de comprendre comment elles régulent l’expression des gènes cibles. Les candidats identifiés feront l’objet d’une analyse plus poussée dans des cellules de LMA par le biais de différentes approches moléculaires.
Objectif
Acute Myeloid Leukemia (AML) is the most frequent cancer of the blood system, with >80% mortality within 5 years of diagnosis. Straightforward clinical decisions are complicated by the genetic complexity of AML. In particular, fusion proteins arising from chromosomal aberrations are recurrently found in AML and often act as strong driver oncogenes. In “Multi-Partner Translocation” (MPT) families, one specific gene is fused to many recipient loci. Due to this modular architecture, MPT families are of particular interest to comparative studies of oncogenic mechanisms. The three most common MPT families in AML represent translocations of the MLL, RUNX1 and NUP98 genes. Despite their clinical significance, the molecular mechanism of transformation remains unknown for the majority of fusion proteins and it is unclear if transforming mechanisms are conserved within and across different MPT families.
We hypothesize that common oncogenic mechanisms of fusion proteins are encoded in physical and genetic cellular interaction networks that are specific to MPT families. We propose to delineate critical common effectors of oncogenic mechanisms in AML driven by MPT families through a comprehensive, comparative, functional analysis of 20 clinically representative MLL-, RUNX1- and NUP98-fusion proteins using a unique experimental pipeline. Characterization of protein interactomes and their effects on gene expression will identify common cellular denominators of MPT families, whose functional contribution will be assessed through pooled shRNA screens in clinically relevant model systems. High-confidence hits will be validated in mouse models and primary cells from AML patients. This project will generate large informative datasets and novel experimental systems that are of relevance for basic and clinical cancer research. It will contribute to improved understanding of oncogenic mechanisms, which may directly impact on diagnostic and therapeutic strategies in the management of AML.
Champ scientifique
- social sciencessociologydemographymortality
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesmathematicspure mathematicsmathematical analysisfunctional analysis
- medical and health sciencesclinical medicineoncologyleukemia
- natural scienceschemical sciencesanalytical chemistrymass spectrometry
Programme(s)
Thème(s)
Régime de financement
ERC-STG - Starting GrantInstitution d’accueil
1210 Wien
Autriche