Differentiation state instability and clonal selection as escape paths from anticancer therapy

Pediatric Acute Lymphoblastic Leukemia (ALL) arises from lymphocyte progenitors and is known to present a hierarchy of cell differentiation, making it a suitable model disease for studying differentiation state instability and cancer stem cells.

We will analyze ALL samples during treatment and at relapsed from the same patient using a novel method that allows RNA sequencing and genomic sequencing in jointly in the same single cells.

Using this method, we will characterize the clonal structure of the leukemia and analyze clonal leukemic cell types in the primary sample of patients which later relapse.

Since we obtain data on both the genotype (genomic sequencing) and gene expression profile (RNA-seq) of each cell, we can trace clonal expansions that are mainly driven by epigenetic factors as well as those driven by genetic alterations.

Based on this map of treatment escape, we will 1) Determine molecular targets for therapy using a gene editing screen and 2) Test the added value of single-cell genomics for diagnostic tests (in collaboration with clinical genetics).

After initial analysis of the ALL data, we will also study solid tumors using the same methods, building a pan-cancer map of lineage-resolved cancer cell types.

The ultimate goal of the project is to gain a deep understanding of the cancer stem cell population in pediatric ALL tumors in a way that will have a direct impact on the treatment and prevention of ALL recurrence.