Autophagy-deficient mice are more susceptible to engrafted leukemogenesis

Chaorong Ge; Ni An; Lei Li; Wen Wei; Li Ji; Na Yuan; Yixuan Fang; Li Xu; Lin Song; Jingyi Zhang; Chenglin Song; Jianrong Wang; Suping Zhang

doi:10.1016/j.bcmd.2019.04.013

Autophagy-deficient mice are more susceptible to engrafted leukemogenesis

Blood Cells Mol Dis. 2019 Jul:77:129-136. doi: 10.1016/j.bcmd.2019.04.013. Epub 2019 Apr 28.

Authors

Chaorong Ge¹, Ni An¹, Lei Li¹, Wen Wei¹, Li Ji¹, Na Yuan¹, Yixuan Fang¹, Li Xu¹, Lin Song¹, Jingyi Zhang¹, Chenglin Song¹, Jianrong Wang², Suping Zhang³

Affiliations

¹ Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Key Laboratory of Stem Cells and Biomedical Materials of Jiangsu Province and Chinese Ministry of Science and Technology, State Key Laboratory of Radiation Medicine and Radioprotection, Soochow University, Suzhou 215123, China.
² Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Key Laboratory of Stem Cells and Biomedical Materials of Jiangsu Province and Chinese Ministry of Science and Technology, State Key Laboratory of Radiation Medicine and Radioprotection, Soochow University, Suzhou 215123, China. Electronic address: jrwang@suda.edu.cn.
³ Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Key Laboratory of Stem Cells and Biomedical Materials of Jiangsu Province and Chinese Ministry of Science and Technology, State Key Laboratory of Radiation Medicine and Radioprotection, Soochow University, Suzhou 215123, China. Electronic address: spzhang@suda.edu.cn.

PMID: 31059942
DOI: 10.1016/j.bcmd.2019.04.013

Abstract

Autophagy is primarily considered as an important survival mechanism for both normal cells and cancer cells in response to metabolic stress or chemotherapy; but the role of autophagy in leukemogenesis is not fully understood. The aim of this study is to explore the role of intrinsic autophagy in the leukemogenesis of B-cell acute lymphoblastic leukemia (B-ALL). In this study, conditional knockout mice Atg7^f/f;Ubc-Cre, in which an autophagy-essential gene Atg7 is universally deleted, were used as recipients, B-ALL cell line 697 was used as donor cells to generate leukemia mouse model. Compared to wild-type mice, Atg7 knockout mice were more susceptible to engrafted leukemogenesis, shown by increase in white blood cells, lymphocytes, and platelets, decrease in HSPC number and its colony-forming unit (CFU). The liver and spleen displayed hepatosplenomegaly and inflammatory cell infiltration. Furthermore, second competitive transplantation revealed dysfunction of the HSPC in Atg7-knockout leukemia mice represented by destructive self-renew ability (CFU) and reconstitution ability including decreased B220, Ter 119 cells, and increased Gr-1 cell percentage. In summary, Mice with universal deletion of Atg7 are more inclined to the occurrence of engrafted human leukemia, which is largely attributed to the deterioration of the function of HSPC in autophagy deficient mice.

Keywords: Autophagy; Conditional knock out mice; Engrafted leukemia; Hematopoietic stem and progenitor cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autophagy / genetics*
Autophagy-Related Protein 7 / deficiency
Cell Transformation, Neoplastic / genetics*
Disease Models, Animal
Genetic Association Studies
Genetic Predisposition to Disease*
Genotype
Leukemia / genetics*
Leukemia / metabolism
Leukemia / pathology
Mice
Mice, Knockout

Substances

Autophagy-Related Protein 7