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Common Oncogenic Mechanisms in Multi-Partner Translocation Families in Acute Myeloid Leukemia

Objective

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.

Field of science

  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins
  • /natural sciences/chemical sciences/analytical chemistry/mass spectrometry
  • /medical and health sciences/clinical medicine/cancer/leukemia

Call for proposal

ERC-2014-STG
See other projects for this call

Funding Scheme

ERC-STG - Starting Grant

Host institution

VETERINAERMEDIZINISCHE UNIVERSITAET WIEN
Address
Veterinaerplatz 1
1210 Vienna
Austria
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 513 990,75

Beneficiaries (2)

VETERINAERMEDIZINISCHE UNIVERSITAET WIEN
Austria
EU contribution
€ 513 990,75
Address
Veterinaerplatz 1
1210 Vienna
Activity type
Higher or Secondary Education Establishments
LUDWIG BOLTZMANN GESELLSCHAFT GMBH

Participation ended

Austria
EU contribution
€ 985 509,25
Address
Nussdorfer Strasse 64 6 Stock
1090 Wien
Activity type
Research Organisations