Atg5-dependent autophagy contributes to the development of acute myeloid leukemia in an MLL-AF9-driven mouse model.
Acute myeloid leukemia (AML) is a hierarchical hematopoietic malignancy originating from leukemic stem cells (LSCs). Autophagy is a lysosomal degradation pathway that is hypothesized to be important for the maintenance of AML as well as contribute to chemotherapy response. Here we employ a mouse model of AML expressing the fusion oncogene MLL-AF9 and explore the effects of Atg5 deletion, a key autophagy protein, on the malignant transformation and progression of AML. Consistent with a transient decrease in colony-forming potential in vitro, the in vivo deletion of Atg5 in MLL-AF9-transduced bone marrow cells during primary transplantation prolonged the survival of recipient mice, suggesting that autophagy has a role in MLL-AF9-driven leukemia initiation. In contrast, deletion of Atg5 in malignant AML cells during secondary transplantation did not influence the survival or chemotherapeutic response of leukemic mice. Interestingly, autophagy was found to be involved in the survival of differentiated myeloid cells originating from MLL-AF9-driven LSCs. Taken together, our data suggest that Atg5-dependent autophagy may contribute to the development but not chemotherapy sensitivity of murine AML induced by MLL-AF9.
Department of Pharmacology, Penn State College of Medicine, Hershey, PA, USA.
Qiang
Q
Liu
Department of Pediatrics, Penn State College of Medicine, Hershey, PA, USA.
Longgui
L
Chen
Department of Pediatrics, Penn State College of Medicine, Hershey, PA, USA.
Jennifer M
JM
Atkinson
Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, PA, USA.
David F
DF
Claxton
Department of Pharmacology, Penn State College of Medicine, Hershey, PA, USA.|Department of Pediatrics, Penn State College of Medicine, Hershey, PA, USA.|Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, PA, USA.
Hong-Gang
HG
Wang
D000818:Animals; D001343:Autophagy / Q000276:immunology*; D000071187:Autophagy-Related Protein 5 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016026:Bone Marrow Transplantation / Q000379:methods*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D017353:Gene Deletion; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D008247:Lysosomes / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D016019:Survival Analysis
C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; C551356:MLL-AF9 fusion protein, mouse; D015514:Oncogene Proteins, Fusion