[994] Lymphomas and leukaemias

Our team aim at discovering new treatments options for hematological malignancies, particularly acute myeloid leukemia (AML) and aggressive lymphomas. We will pursue our team leader’s works on the role of the AMP-activated protein kinase (AMPK) – a major regulator of energy metabolism – in AML, having demonstrated the anti-leukemic effects of metformin, and developed a specific AMPK activator, the GSK621 compound with potent anti-leukemic activity. Our second project concerns the FLT3 kinase, mutated in up to 30 % of AML cases with adverse prognostic impact. These mutations are actionable by targeted therapies (TKI: tyrosine kinase inhibitors) with significant but transient clinical activity. We adapted a new method of analysis at the genome scale by the CRISPR/Cas9 technology, allowing unbiased search for new genes involved in TKI resistance, which will eventually pave the way for new therapeutic strategies in FLT3-mutated AML. Our third project concerns the search for genetic alterations leading to oncogenic RAS activation in AML. Our preliminary findings unravel mutations and deletions of the NF1 gene, and the exquisite sensitivity of these cells to a MEK inhibitor (trametinib). These ongoing projects will be enriched soon by the implementation of humanized mouse models of AML, to study intra-tumour clonal diversity and leukemic stem cells biology.