Descripción del proyecto
Mecanismos esenciales comunes en casos de translocación en la leucemia mielógena aguda
La leucemia mielógena aguda (LMA) es una neoplasia hemática con bajas tasas de supervivencia, donde las decisiones clínicas se dificultan por la complejidad genética de la LMA, lo cual repercute en las opciones de tratamiento personalizado. Las anomalías cromosómicas crean proteínas de fusión, que actúan como potentes oncogenes. Las reordenaciones cromosómicas se incluyen en familias de translocaciones multipartitas (TMP) con un gen específico fusionado a una serie de receptores. El equipo del proyecto ONCOMECHAML, financiado por el Consejo Europeo de Investigación, pretende identificar los componentes esenciales comunes de la oncogénesis en las familias de TMP de la LMA, mediante un análisis comparativo de veinte proteínas de fusión diferentes. El objetivo es encontrar las proteínas asociadas a la proteína de fusión y comprender cómo regulan la expresión de los genes diana. Los candidatos identificados se seguirán analizando en células de LMA mediante distintos métodos moleculares.
Objetivo
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.
Ámbito científico
- social sciencessociologydemographymortality
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesmathematicspure mathematicsmathematical analysisfunctional analysis
- medical and health sciencesclinical medicineoncologyleukemia
- natural scienceschemical sciencesanalytical chemistrymass spectrometry
Programa(s)
Régimen de financiación
ERC-STG - Starting GrantInstitución de acogida
1210 Wien
Austria