The emergence of relapse resistant to chemotherapy is the major obstacle preventing the cure of

cancer. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy that accounts for

15% of pediatric and 25% of adult acute lymphoblastic leukemia cases. Although genomic studies

have shed light on the genetic mechanisms driving disease development as well as recurrence

following therapy, this knowledge has so far not been translated in optimized treatment. Indeed,

currently T-ALL patients are still treated with intensive chemotherapeutic regimens with long-term

side effects. Eventually, relapse occurs in 15% of pediatric and 40% of adult T-ALL patients,

associated with very poor outcome. The finding that T-ALL relapse arises from a subclone that was

already present at diagnosis poses the intriguing question which features allow these subclones in

particular to survive chemotherapy. Several studies point to a role for cancer stem cells, a

dormant tumoral subpopulation characterized by self-renewal and resistance to therapy. By

combining flow cytometry-based functional assays with single cell DNA and RNA sequencing we

aim to integrate functional and genetic features of chemoresistant tumor cells in both diagnostic

and relapse T-ALL samples. By studying patient T-ALL samples in co-culture systems and in primary

xenograft models we will assess how T-ALL subclones are selected by particular (combinations of)

chemotherapeutic compounds.