ALLRUN · Modeling TEL/AML1 childhood lymphoblastic leukemia in zebrafish
FP7 — People (Marie Curie Actions)
- Duration
- 2012-02-01 → 2016-01-31
- EU contribution
- €100,000
- Participants
- 1
- Scheme
- MC-CIG
Lines connect the coordinator with its partners.
Results in brief
Modeling TEL/AML1 childhood lymphoblastic leukemia in zebrafish
1/ Summary description of the project objectives Acute lymphoblastic leukemia is the most common childhood cancer. It is diagnosed in about 5000 children in Europe every year. The most frequent B-type acute lymphoblastic leukemia, called ETV6/RUNX1 (also known as TEL/AML1), is due to a genetic rearrangement that occurs during fetal development and produces an abnormal but functional protein ETV6/RUNX1. To date, most treatment protocols result in a good outcome for ETV6/RUNX1 leukemic patients, although current treatments increase the risk of secondary cancer up to 10% at 15 years after the end of the treatment. The pathogenesis of ETV6/RUNX1 fusion protein is still not well characterized. Understanding the pathogenesis of ETV6/RUNX1 is the question addressed in the present project. Objectives We proposed to study the role of transcription factors RUNX1 and ETV6/RUNX1 in leukemogenesis of ETV6/RUNX1 childhood leukemia. To that end: 1. We determined which isoforms of RUNX1 are overexpressed, and identified their post-translational modifications in ETV6/RUNX1 acute lymphoblastic leukemia. 2. We elucidated the mechanisms that control genetics and epigenetics regulation of RUNX1. 3. We characterized the cooperation between RUNX1 and ETV6/RUNX1, providing clues to understand mechanisms implicated in leukemia. 2/ Description of the work performed since the beginning of the project Tools required to achieve our goals have been set up: cell culture and analysis of cell phenotypes, zebrafish model for leukemia, etc. We have established new collaborations with European and US teams. Significant results have been achieved for the three objectives. 3/ Description of the main results achieved so far We have identified the isoform that is overexpressed in leukemic patients for the cohort used in Gandemer V et al, BMC Genomics 2007. We have identified some phosphorylations for RUNX1 in the pre-B cells. We have identified some transcriptional partners of RUNX1 and ETV6/RUNX1 and validated them. We have generated double transgenic ETV6/RUNX1+RUNX1 zebrafish. Finally, we have characterized the genomic remodeling induced by RUNX1 in the presence of ETV6/RUNX1. An article about leukemia cells dissemination has been published in Blood, and another manuscript is in preparation. 4/ Expected final results and their potential impact and use (including the socio-economic impact and the wider societal implications of the project so far). The results of our work are expected to assign a novel major role of the normal allele of RUNX1 in ETV6/RUNX1-associated B cell acute lymphoblastic leukemia. We have a better understanding of how both transcription factors ETV6/RUNX1 and RUNX1 cooperate at the chromatin level to modulate gene expression and may give rise to leukemia. Moreover, identification of transcriptional partners of RUNX1 and ETV6/RUNX1 controlling their transcriptional activities enlarges the panel of potential therapeutics targets against leukemia. Our work may pave the road to new therapeutics targets. 5/ Integration I have obtained a permanent position as Research Scientist class 1 (chargée de Recherche classe 1) at The Centre National de la Recherche Scientifique CNRS in April 2012. It was one of the goals of this ‘integration period’ supported by the CIG grant. I have obtained funding for my research projects. I have attended many workshops and seminars in hematology, zebrafish disease models. I also teach in my field of expertise at the Université de Rennes 1 and Université de Bretagne Occidentale. I supervises two PhD student, and Master students. I review original articles for international journals, and have responsibilities of scientific expertise at national and European level. This project is now part of the Rennes comprehensive cancer care center, named Cancer- Microenvironment and Innovation CAMIn, directed by Pr. Thierry Lamy de la Chapelle and Pr. MD Galibert-Anne.
Data: CORDIS, © European Union
Project objective
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.
Original text from CORDIS.
Participants
- UNIVERSITE DE RENNES I · RENNES CEDEXCoordinatorFrance
Links
Data: CORDIS, © European Union