TY - JOUR
T1 - Oncogenic KIT mutations induce STAT3-dependent autophagy to support cell proliferation in acute myeloid leukemia
AU - Larrue, Clément
AU - Heydt, Quentin
AU - Saland, Estelle
AU - Boutzen, Héléna
AU - Kaoma, Tony
AU - Sarry, Jean Emmanuel
AU - Joffre, Carine
AU - Récher, Christian
N1 - Funding Information:
We thank all members of the GAEL (Gaël Adolescent Espoir Leucémie) association. We acknowledge Valérie Duplan-Eche, Fatima L’Faqihi-Olive, and Manon Farcé for their technical assistance in the flow-cytometry core facilities at INSERM UMR1043 and INSERM UMR1037. We are grateful to Laetitia Ligat for technical assistance in the imagery facility at INSERM UMR1037. This work was supported by Ligue nationale contre le Cancer and Clément Larrue is a recipient of the Ligue Nationale contre le Cancer. We thank Patrice Dubreuil (CRCM, Marseille, France) for providing the specific leukemic cell lines: TF-1 and TF-1 KITD816V. This work received a grant from the French government under the “Investissement d’avenir” program (ANR-11-PHUC-001), the Institut National du Cancer (INCA-PLBIO 2012–105), and the InnaBioSanté foundation (RESISTAML project).
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/8/1
Y1 - 2019/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85069057293&partnerID=8YFLogxK
U2 - 10.1038/s41389-019-0148-9
DO - 10.1038/s41389-019-0148-9
M3 - Article
AN - SCOPUS:85069057293
SN - 2157-9024
VL - 8
JO - Oncogenesis
JF - Oncogenesis
IS - 8
M1 - 39
ER -