Unravelling Pathobiological Molecular Mechanisms of T-Cell Acute Lymphoblastic Leukemia

T-cell acute lymphoblastic leukemia (T-ALL) represents 10-15% of pediatric acute leukemias. Despite major therapeutic improvements due to treatment intensification and refined risk-adapted stratification during the past decade, ~30% of T-ALL cases relapse with very poor prognosis. T-cell transformation is characterized by aberrant expression of oncogenic transcription factors combined with inactivation of tumor suppressor genes (e.g. PTEN, CDKN2A) and/or activation of the NOTCH1 pathway. The ectopic expression of oncogenes is typically caused by chromosomal rearrangements that place oncogenes under the control of T-cell specific promoters or enhancer elements.

This thesis aimed to:
1) identify additional PTEN-inactivating events as novel type-B mutations that may provide survival and proliferation advantage to (pre)-leukemic cells, and understand their clinical impact in T-ALL;
2) establish an in vitro co-culture system (OP9-DL1) that supports T-cell development from human umbilical cord blood-derived hematopoietic stem cells (HSCs), with the intention of defining distinct human T-cell development stages in relation to the underlying transcriptional programs and expression of cell surface markers;
3) optimize a lentivirus system that supports transduction and stable expression of oncogenes in human and mouse HSCs and
4) study the impact of ETP-ALL expressed oncogenes (such as MEF2C, LYL1 or LMO2) on human T-cell development using the OP9-DL1 in vitro system