Despite a high rate of complete remission after chemotherapy, the prognosis is poor in human acute myeloid leukemia (AML) due to the high frequency of relapses. These relapses are mainly caused by the growth of resistant leukemic cells able to adapt their metabolism to survive. Thus, additional studies are needed to understand the mechanisms involved and develop new treatments to eradicate resistant AML cells. We hypothesized that this adaptation is controlled by autophagy, a catabolic process involved in cancer biology regulation and metabolism. While previous studies on autophagy and tumor growth mainly focused on tumor autophagy, host/microenvironment autophagy has also been recently implicated in tumor growth promotion by supplying important substrates. However, to date, neither its role in therapeutic resistance nor its relevance in AML development has yet been studied.

Combining complementary models: in vitro co-culture system and in vivo genetically engineered mouse models with AML cell lines and primary AML patient samples, we investigated whether host autophagy, especially bone marrow autophagy, can support AML growth and investigated the mechanisms involved. In vitro, AML cell lines and primary patient samples were co-cultured with mesenchymal cells deficient for autophagy (MS5 shAtg5 or shFip200). In vivo, AML cells were injected into immunocompetent (C57B6J) or immunodeficient (NSG) inducible whole-body autophagy-deficient mice (Cre+/ERT2; Atg7flox/flox). AML cell viability and tumor burden were assessed by flow cytometry following treatment with the chemotherapy Cytarabine, Idarubicine or the targeted therapy Venetoclax or Azacytidine.

We first showed that, host autophagy promotes AML cell growth without affecting cell homing in vivo. Similar results were obtained in immunocompetent and immunodeficient mice suggesting that immune response is not involved. We also demonstrated that loss of host autophagy sensitizes AML cells to chemotherapy as well as targeted therapy in vitro. In vivo preliminary data also suggest that host autophagy participates in AML therapeutic resistance. In addition, we observed that host autophagy is required for AML therapeutic resistance through factor secretion. Metabolomics analysis of autophagy-deficient and wild-type mice revealed that host autophagy regulates circulating metabolites especially pyrimidine bases and amino acids that seem to be required for AML resistance.

Our findings establish host autophagy as a key determinant of AML progression and therapeutic resistance and identify new potential targets to eradicate AML resistant cells. Future experiments aim to better decipher the exact mechanisms involved. Thus, targeting host autophagy or the underlying mechanisms represent promising therapeutic new strategies to overcome AML patient relapses and improve their survival.