Changes in chromosome numbers in pediatric leukemia: how, why and when?

Aneuploidy, i.e., changes in chromosome numbers, is a common phenomenon in cancer cells.

In the proposed project I will study two types of aneuploid pediatric acute lymphoblastic leukemia (ALL): hyperdiploid (gain of chromosomes) and hypodiploid (loss of chromosomes) ALL.

In spite of clinical differences between these two genetic subtypes, the underlying driver mechanisms are believed to be similar.

I will build on previous results from my group showing that the chromosomal copy number changes are early events and the main driver of disease.

In the first study, I will perform Micro-C, a form of Hi-C, in a large cohort of pediatric ALL to study how aneuploidy affects chromatin 3D organization and to further explore the link to low CTCF levels that we have previously discovered.

In the second study, I will perform single cell sequencing and CRISPR screens to identify genes in gained chromosomes that directly affect leukemogenesis.

Lastly, I will address heterogeneity in the mechanism of how aneuploidy arises and identify clinically relevant subgroups.

ALL is the most common type of malignancy in children and aneuploidy constitutes an underexplored type of genetic aberration in precision medicine.

My results will contribute to a deeper understanding of how changes in chromosome numbers affect tumorigenesis and may provide novel avenues for targeted treatment.