Final Report Summary - ALLRUN (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.
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.