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Investigating Trib2-induced Acute Myeloid Leukaemia

Objectif

Acute Myeloid Leukemia (AML) is a poorly treatable leukemia in which a limited set of genes are involved. Trib2 is a gene that has not previously been associated with leukemia. My goal is to understand the pathogenesis of Trib2-induced acute myelogenous leukemia (AML). I identified Trib2 as a novel leukomogen that efficiently induces a clonal, transplantable AML in mice. Trib2 inhibits C/EBPalpha to cause AML, and elevated Trib2 expression associates with a cluster of human AML samples that have disrupted C/EBPalpha. This proposal will identify genetic events that cooperate with Trib2 and the Trib2 structural requirements for AML induction. Aim 1 will define the structural and functional domains of Trib2 that contribute to AML, and the domains required for C/EBPalpha inhibition. This will set the stage for Aim 2, which will identify the biochemical mechanism of Trib2-mediated C/EBPalpha degradation, and the mechanism involved in the Trib2-mediated degradation of other potential proteins. Aim 3 will ascertain cooperating events that contribute to Trib2-induced AML. The clonality of the Trib2-induced tumors suggests that the proviral integration site itself may activate genes that cooperate with Trib2. I will identify these proviral integration sites and determine whether genes at these sites synergize with Trib2 in AML pathogenesis. Together, my studies will reveal new pathogenic mechanisms and therapeutic opportunities in this aggressive cancer, which is not currently curable in the majority of patients.

Appel à propositions

FP7-PEOPLE-IRG-2008
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Coordinateur

UNIVERSITY COLLEGE CORK - NATIONAL UNIVERSITY OF IRELAND, CORK
Contribution de l’UE
€ 100 000,00
Adresse
WESTERN ROAD
T12 YN60 Cork
Irlande

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Région
Ireland Southern South-East
Type d’activité
Higher or Secondary Education Establishments
Contact administratif
Mary Cusack (Ms.)
Liens
Coût total
Aucune donnée