Carine JOFFRE & Laura POILLET
LEUKEMIC AND HOST AUTOPHAGY, A MAJOR PLAYER IN THERAPEUTIC RESISTANCE OF AML CELLS.
Autophagy, which literally means “eating oneself”, is not only a degradation mechanism put in place by the cell to eliminate organelles and protein aggregates, it is also a process involved in the establishment of resistance mechanisms in various cancers. Autophagy is an effective response to various nutritional and environmental stresses such as chemotherapy. It also allows the cell to meet its energy needs in conditions of deficiency, by recycling the nutrients necessary for basic cellular functions and thus sustaining the metabolism. Autophagy is a major player in the biology of AML. Indeed, we have shown that FLT3-ITD and KITD816V mutant receptor tyrosine kinases increase the basal level of autophagy necessary for the proliferation and survival of these cells. We have also demonstrated the existence of a regulatory loop between autophagy and mitochondria. Autophagy, by degrading fatty acids, provides the necessary substrates for mitochondrial activity which thus supports the proliferation of leukemic cells in vitro and in vivo. Furthermore, an emerging literature demonstrates that autophagy in a given cell significantly impacts the fate/behavior of neighboring cells. Thus, autophagy present in cells of the tumor microenvironment, host autophagy, has recently been implicated in the growth of various solid cancers through the regulation of their metabolism. However, to date, no study has been conducted on its role in the mechanisms of resistance to treatments. Thus, neither its role in resistance mechanisms nor its importance in leukemic development have been studied yet.
In short, there are no convincing studies to date linking leukemic or host autophagy to therapeutic resistance in AML. Furthermore, our team has recently demonstrated that treatment resistance in leukemic cells requires an adaptation of their energy metabolism. We therefore hypothesize that this adaptation and the associated resistance mechanisms are controlled by leukemic and/or host autophagy.
In order to define the involvement of autophagy in resistance to chemotherapies and targeted therapies in AML, we are implementing mainly two lines of research consisting in:
- To study the capacity of autophagy to regulate cellular signaling pathways, in particular those controlling different metabolic pathways;
- Evaluate the potential role of host autophagy in tumor progression and resistance mechanisms.