The role of CTCF and cohesin in leukemia development

High hyperdiploid acute lymphoblastic leukemia (ALL) is characterized by chromosomal gains. How these extra chromosomes are gained and how they affect the cell remain largely unknown.

We have recently reported that hyperdiploid leukemia has low levels of CTCF and cohesin, two key factors in maintaining genetic stability and regulating gene expression. Here, we will investigate how this affects leukemogenesis.

Firstly, we will use single cell whole genome sequencing to determine whether hyperdiploid ALL harbor chromosomal heterogeneity, indicative of chromosomal instability that could be linked to low cohesin levels.

Secondly, we will address the hypothesis that the bulk of the extra chromosomes arise by an initial simultaneous gain followed by fine-tuning via clonal selection to optimize fitness.

This will be done by determining individual chromosomal fitness values by investigating the age of chromosomes and by studies of clonal evolution in xenografts.

These studies will lay the ground for in silico modeling of hyperdiploidy development using data from a large patient cohort.

Thirdly, since CTCF and cohesin are involved in chromatin 3D organization and thereby gene regulation, we will use Hi-C and functional analyses to identify dysregulated driver genes. High hyperdiploid ALL is one of the most common malignancies in childhood.

This project will increase our understanding of the underlying leukemogenic process in this leukemia and may identify new therapeutic targets.