TY - JOUR
T1 - Atg5-dependent autophagy contributes to the development of acute myeloid leukemia in an MLL-AF9-driven mouse model
AU - Liu, Qiang
AU - Chen, Longgui
AU - Atkinson, Jennifer M.
AU - Claxton, David F.
AU - Wang, Hong Gang
N1 - Funding Information:
This work was supported by National Institutes of Health Grant CA171983, Hyundai Hope On Wheels Grant, the Lois High Berstler Endowment Fund, and the Four Diamonds Fund of the Pennsylvania State University College of Medicine. We thank Dr Robert Paulson (Penn State University, PA, USA) for kindly providing cells and reagents and for critical reading of the manuscript. We thank Yoshinori Takahashi (Penn State College of Medicine, PA, USA) and Nikolaos Tsotakos (Penn State College of Medicine, PA, USA) for critical reading of the manuscript. We thank Nate Sheaffer, Joseph Bednarzyk, and Jade Vogel from the Penn State Hershey Flow Cytometry Core Facility for assistance with flow cytometry analysis and cell sorting.
Funding Information:
Acknowledgements. This work was supported by National Institutes of Health Grant CA171983, Hyundai Hope On Wheels Grant, the Lois High Berstler Endowment Fund, and the Four Diamonds Fund of the Pennsylvania State University College of Medicine. We thank Dr Robert Paulson (Penn State University, PA, USA) for kindly providing cells and reagents and for critical reading of the manuscript. We thank Yoshinori Takahashi (Penn State College of Medicine, PA, USA) and Nikolaos Tsotakos (Penn State College of Medicine, PA, USA) for critical reading of the manuscript. We thank Nate Sheaffer, Joseph Bednarzyk, and Jade Vogel from the Penn State Hershey Flow Cytometry Core Facility for assistance with flow cytometry analysis and cell sorting.
Publisher Copyright:
© The Author(s) 2016.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
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U2 - 10.1038/cddis.2016.264
DO - 10.1038/cddis.2016.264
M3 - Article
C2 - 27607576
AN - SCOPUS:85026589114
SN - 2041-4889
VL - 7
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 9
M1 - e2361
ER -