Oncogenic KIT mutations induce STAT3-dependent autophagy to support cell proliferation in acute myeloid leukemia.
Clément LarrueQuentin HeydtEstelle SalandHéléna BoutzenTony KaomaJean-Emmanuel SarryCarine JoffreChristian RecherPublished in: Oncogenesis (2019)
Autophagy is associated with both survival and cell death in myeloid malignancies. Therefore, deciphering its role in different genetically defined subtypes of acute myeloid leukemia (AML) is critical. Activating mutations of the KIT receptor tyrosine kinase are frequently detected in core-binding factor AML and are associated with a greater risk of relapse. Herein, we report that basal autophagy was significantly increased by the KITD816V mutation in AML cells and contributed to support their cell proliferation and survival. Invalidation of the key autophagy protein Atg12 strongly reduced tumor burden and improved survival of immunocompromised NSG mice engrafted with KITD816V TF-1 cells. Downstream of KITD816V, STAT3, but not AKT or ERK pathways, was identified as a major regulator of autophagy. Accordingly, STAT3 pharmacological inhibition or downregulation inhibited autophagy and reduced tumor growth both in vitro and in vivo. Taken together, our results support the notion that targeting autophagy or STAT3 opens up an exploratory pathway for finding new therapeutic opportunities for patients with CBF-AML or others malignancies with KITD816V mutations.
Keyphrases
- cell death
- cell proliferation
- signaling pathway
- acute myeloid leukemia
- cell cycle arrest
- induced apoptosis
- endoplasmic reticulum stress
- pi k akt
- oxidative stress
- tyrosine kinase
- allogeneic hematopoietic stem cell transplantation
- cell cycle
- free survival
- dendritic cells
- drug delivery
- acute lymphoblastic leukemia
- metabolic syndrome
- bone marrow
- epidermal growth factor receptor
- cancer therapy
- small molecule
- immune response
- adipose tissue
- intensive care unit
- high fat diet induced