Grant: Operating Grant: TRANSCAN-3

Defined as the most frequent pediatric cancer, B-ALL is a multi-step disease from which several oncogenic subgroups have been defined based on the identity of the initial oncogenic events. Chemotherapy efficiently induces long-term remission but is associated with severe side effects and the development of second malignant neoplasms in 15-20% of patients. Genome-wide analyses offered novel insights regarding the signaling pathways altered in this disease and led to the discovery of new therapeutic opportunities. However, unmet medical needs remain for this complex disease and research is ongoing to identify effective preventive strategies that could potentially save children from developing leukemia or having to receive toxic treatments. Based on recent evidence, we hypothesize that a combination of cell-intrinsic and environmental epigenetic cues configure the 'tipping point' at which self-reactive B cells acquire the necessary potential to undergo malignant transformation. Using murine models that faithfully mimic childhood leukemia, we will identify candidate epigenetic biomarkers and signatures associated with the conversion of a pre-leukemic to a leukemic cell clone that can eventually be used as risk markers. Very originally, we will investigate how different environmental exposures can promote the conversion to a leukemic stage. We will also benefit from a novel 3D human BM micro physiological system to assess in situ the importance of these epigenetic traits during the dialogue of pre-leukemic cells with their medullary niche. Altogether, this project should allow the identification of the most robust epigenetic events involved in priming normal B-cells to become pathogenic, thus providing novel biomarkers for detection of at-risk clones in patients and potentially candidates for therapeutic intervention.