The widespread deregulation of gene expression in acute childhood leukemia

Submitted on Wed, 11/02/2016 - 08:53

Acute leukemia is the most common cancer in children. A quarter of the patients exhibit an aberrant gene fusion, which already emerges during embryonal development and leads to the fusion of two important hematopoietic transcription factors (the so called ETV6-RUNX1 fusion). This fusion was already identified two decades ago, but its role has remained elusive. In a new Finnish study, the transcriptional consequences of the expression of ETV6-RUNX1 fusion were explored genome-wide.

In the study, an inducible cell model was generated allowing transient and controlled expression of the ETV6-RUNX1 fusion. After the induction of the fusion, transcriptional changes were followed up by using a modern GRO-seq method that allows genomic-wide and simultaneous mapping of the expression of gene bodies and their regulatory elements. The observed changes were further validated in two separate leukemia patient data sets.  

Changes observed in hundreds of transcripts

“It is intriguing that the ETV6-RUNX1 fusion especially repressed such genomic areas that are relevant to the proper differentiation of B cells from progenitors,” says the first author of the study, doctoral researcher Susanna Teppo from the School of Medicine at the University of Tampere.

The induction of the ETV6-RUNX1 fusion altered the expression of approximately two hundred genes and revealed dynamic changes in previously unknown regulatory elements.

“Intriguingly, marked alterations were found in the so called enhancer sequences whose role is poorly understood in leukemias, but which are crucial for the timely expression of gene bodies. This just points out the complexity of the regulation and its disturbances in leukemic cells,” Teppo explains.

“In addition, genes that are known to participate in cellular signalling and adhesion were markedly downregulated, possibly hinting at problems in communication and migration in the surrounding microenvironment,” Teppo continues.

The study was led by Docent Olli Lohi at the University of Tampere in close collaboration with the research group led by Associate Professor Merja Heinäniemi at the University of Eastern Finland. The study also involved research groups at the University of Uppsala (Sweden) and the University of Montreal (Canada).

The study was published in Genome Research,
http://www.ncbi.nlm.nih.gov/pubmed/27620872

Genome-wide repression of eRNA and target gene loci by the ETV6-RUNX1 fusion in acute leukemia
http://dx.doi.org/10.1101/gr.193649.115

For more information, please contact:
M.Sc. Susanna Teppo, tel. +358 50 318 6249, susanna.teppo@uta.fi
Adjunct Professor Olli Lohi, tel. +358 3 3116 7836, olli.lohi@uta.fi