Etude de l’importance de la protéine synténine des cellules blastiques dans la progression des leucémies myéloïdes aigues

AML is characterized by the clonal expansion of hematopoietic cells at distinctive stages of differentiation and originate from leukemic stem cells (LSCs) located within the bone marrow (BM). Within BM, leukemic cells both hijack/invade the hematopoietic stem cell niches and instruct/educate BM stromal cells to support leukemia. While direct cell-cell contact, and conventional chemokine- and cytokine-mediated interactions are all known contributors of the leukemia-stroma crosstalk, these mechanisms fail to fully explain how leukemic invasion results in niche remodeling. Currently, the notion that nanoparticles (or exosomes) play an important role in ‘cancer crosstalk’ is widely accepted (Fares et al., Cell Adh Migr 2017). Different types of exosomes, which contain specific material that is commonly designated as cargo, can be isolated from body fluids. Cargo transfer to cells regulates gene expression and alters the fate of target cells. Although several studies have demonstrated the role of exosomes in the progression of AML, as well as AML resistance to treatment (Horiguchi et al., Blood 2014 ; Kumar et al., Leukemia 2018), the associated molecular mechanisms remain unknown.
Our lab has identified a molecular machine, supported by the PDZ protein syntenin, which regulates the biogenesis of a specific subclass of exosomes (Fares et al., Cell Adh Migr 2017). Syntenin is highly expressed during early development and its protein levels are abnormally elevated in several types of solid cancer. Some studies even propose that the levels of syntenin protein in the tumor might constitute a marker of disease aggressiveness. Interestingly, syntenin is also known to be involved in signaling pathways that regulate the hematopoietic compartment. We thus launched a study of syntenin in the progression of leukemia, a disease in which the role of syntenin was never investigated and remains to be established.
Methodology : Preclinical human AML models depleted for syntenin expression have already been generated by using CRISPR/cas9-technology. The student will investigate, by various in vitro and in vivo assays, how syntenin levels in cells and exosomes evolve with leukemia aggressiveness. He/she will gain experience with cell culture, co-culture, exosome purification, nanoparticle tracking, Western blot analysis and animal approaches.