Oncogenic KIT mutations induce STAT3-dependent autophagy to support cell proliferation in acute myeloid leukemia

Clément Larrue,Christian Récher,Quentin Heydt,Héléna Boutzen,Tony Kaoma,Estelle Saland,Carine Joffre,Jean-Emmanuel Sarry

doi:10.1038/s41389-019-0148-9

Abstract

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.

Highlights

Autophagy is an adaptive and protective cellular program activated during nutrient deprivation, growth factor withdrawal, or metabolic stress to maintain cellular homeostasis and recycle damaged organelles[1]
KRASG12D in solid tumors[8,9,28,29] or BCR-ABL in chronic myelocytic leukemia[11] and FLT3-ITD in AML16, our study shows that activating mutations of the tyrosinekinase receptor KIT triggers autophagy and supports cell proliferation and survival in acute myeloid leukemia (AML) cells
Very recent insights into the AML cell metabolism have revealed that several metabolic pathways regulated by autophagy, are crucial for AML cell growth and survival

Summary

Introduction

Autophagy is an adaptive and protective cellular program activated during nutrient deprivation, growth factor withdrawal, or metabolic stress to maintain cellular homeostasis and recycle damaged organelles[1]. This dynamic process involves the rearrangement of subcellular membranes in order to sequester organelles or long-lived proteins and to release these contents into the lysosomal machinery for degradation and recycling. Defects in autophagy are associated with various diseases including cancer[2]. It has recently been proposed that autophagy is required for leukemic development, as invalidation of Atg[7] or Atg[5] in a murine Mll-Enl leukemic model impaired tumor growth[13] and involved in resistance to chemotherapy[13,14]

Methods

Results

Conclusion