This project aims to capture the heterogeneity of acute lymphoblastic leukemia (ALL) MRD, and identify characteristics of ALL MRD during chemotherapy treatment. The researcher will identify and characterize residual patient ALL cells during chemotherapy treatment by single cell multiomics.
This project aims to capture the molecular heterogeneity of B-cell acute lymphoblastic leukemia (B-ALL) measurable residual disease (MRD) and identify the characteristics of resistant leukemic cells that survive chemotherapy treatment.
To study these rare residual cells, patient-derived xenograft (PDX) models are established in immunodeficient NSG mice both from clinical MRD follow-up samples and by treating diagnosis-based PDX models with induction chemotherapy to mimic the MRD state. This provides sufficient residual leukemic cells to perform integrative single-cell analyses. MRD cells are characterized simultaneously at the transcriptional, epigenetic, and protein levels using scRNA-seq and CITE-seq (10x Genomics), targeted long-read sequencing for clonal tracking. The project focuses on high hyperdiploid B-ALL, a subtype that accounts for approximately 25% of pediatric ALL cases and a substantial fraction of relapses.
Candidate genes and pathways identified from single-cell data are functionally validated in an ex vivo MSC stromal co-culture system that recapitulates the bone marrow niche, using focused CRISPR dropout screens and drug testing. The most promising targets are then confirmed in vivo through focused CRISPR dropout screens in PDX mouse models under chemotherapy conditions. In collaboration with DC6, the project also tests sequential therapeutic interventions based on the "evolutionary trap" approach, exploiting the molecular vulnerabilities that MRD cells acquire through their adaptation to chemotherapy.
Host:
VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium.
Supervisor:
Prof. Dr. Jan Cools
Doctoral Candidate