Modeling TEL/AML1 childhood lymphoblastic leukemia in zebrafish
Start date: Feb 1, 2012,
End date: Jan 31, 2016
Acute lymphoblastic leukemia is the most common childhood malignancy and is diagnosed in about 5000 children in Europe every year. The most frequent B-type acute lymphoblastic leukemia, called TEL/AML1, is due to a chromosomal translocation that results in the fusion of two transcription factors, TEL with AML1 (also called RUNX1). Most treatments of TEL/AML1 acute lymphoblastic leukemia result in a good outcome, although some patients suffer very late relapse which cannot be anticipated at the diagnosis. Anticipating and treating the late relapse is a real therapeutic challenge.Understanding the pathogenesis of TEL/AML1 will allow anticipating the late relapse and proposing adjusted therapy and new targeted therapy.TEL/AML1 translocation leads to increased expression of the normal allele of AML1. AML1 is a major transcription factor for hematopoiesis. AML1 impairments are found in many acute leukemia: lymphoblastic, myeloid, and megakaryoblastic. Finally, amplifications of AML1 in other B- acute lymphoblastic leukemia are suspected to worthen the prognosis.My goal is to address the question of TEL/AML1-associated leukemogenesis by characterizing the cooperation between AML1 and TEL/AML1 in an innovative pathophysiology approach. We will combine molecular and cellular biology approaches with physiological approach in zebrafish, and validation in human samples. We will use TEL/AML1 transgenic zebrafish that is the only model of TEL/AML1 leukemia available. We will focus on studying the rate of onset of leukemia, change in proliferation, survival and differentiation of lymphoblasts in dual transgenic TEL/AML1 and AML1 zebrafish. We will validate the results in a large cohort of human TEL/AML1 pre-B acute lymphoblastic leukemia samples.This study will provide new insights on how AML1, a key player of hematopoiesis, affects the molecular pathogenesis of TEL/AML1-induced leukemia. The zebrafish model will permit us to identify major players required for leukemia.
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