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Modeling TEL/AML1 childhood lymphoblastic leukemia in zebrafish

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Zebrafish model for childhood leukaemia

Acute lymphoblastic leukaemia is the most common form of childhood cancer. Delineating its molecular aetiology requires novel disease models.

Health

The most frequent type of acute lymphoblastic leukaemia emerges from the genetic rearrangement between the ETV6 and RUNX1 genes that leads to the production of an abnormal but functional protein ETV6/RUNX1. Although treatment of these patients has a good outcome, nearly 10 % will relapse 15 years later. To improve these statistics, researchers need to characterise the pathogenesis of the ETV6/RUNX1 fusion protein. Towards this goal, scientists on the EU-funded ALLRUN (Modeling TEL/AML1 childhood lymphoblastic leukemia in zebrafish) project set out to study the role of transcription factors RUNX1 and ETV6/RUNX1 in leukaemogenesis. For this purpose, they developed a zebrafish model and studied the cooperation between RUNX1 and ETV6/RUNX1 in leukaemia. RUNX1 is a key transcription factor in haematopoiesis and is associated with many types of acute leukaemia. Researchers determined which RUNX1 isoforms were expressed in patients and identified post-translational modifications as well as transcriptional partners of RUNX1, widening the panel of potential therapeutic targets against leukaemia. In zebrafish, they delineated the genetic modifications and remodelling induced by RUNX1 in the presence of ETV6/RUNX1. The results indicated that both transcription factors ETV6/RUNX1 and RUNX1 cooperated at the chromatin level to modulate gene expression. Overall, the results of the ALLRUN study unveiled a novel major role of the normal allele of RUNX1 in ETV6/RUNX1-associated B cell acute lymphoblastic leukaemia. Elucidation of the genetic and epigenetic regulation of RUNX1 might open new avenues for therapeutic interventions in children with leukaemia.

Keywords

Zebrafish, acute lymphoblastic leukaemia, ETV6, RUNX1

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