title: Rictor/mammalian target of rapamycin 2 regulates the development of Notch1 induced murine T-cell acute lymphoblastic leukemia via forkhead box O3.
abstract: Mammalian target of rapamycin (mTOR) is composed of two distinct biochemical complexes, mTORC1 and mTORC2. In response to nutrients and growth factors, mTORC1 is known to control cellular growth by regulating the translational regulators S6 kinase 1 and 4E binding protein 1, whereas mTORC2 mediates cell proliferation and survival by activating Akt through phosphorylation at Ser473. Studies have shown that the deregulation of mTORC2 leads to the development of myeloproliferative disorder and leukemia in the phosphatase and tensin homolog deleted on chromosome ten (PTEN)-deleted mouse model. However, the mechanism by which mTORC2 specifically affects leukemogenesis is still not fully understood. Here, we investigated the role of mTORC2 in NOTCH1-driven T-cell acute lymphoblastic leukemia (T-ALL) in a Rictor-deficient mouse model. We found that, by deleting Rictor, an essential component of mTORC2, leukemia progression was significantly suppressed by arresting a greater proportion of Rictor(△/△) leukemic cells at the G0 phase of the cell cycle. Furthermore, the absence of Rictor led to the overexpression of chemotaxis-related genes, such as CCR2, CCR4 and CXCR4, which contributed to the homing and migration of Rictor-deficient T-ALL cells to the spleen but not the bone marrow. In addition, we demonstrated that inactivation of mTORC2 caused the overexpression of forkhead box O3 and its downstream effectors and eased the progression of leukemia in T-ALL mice. Our study thus indicates that forkhead box O3 could be a potential drug target for the treatment of T-ALL leukemia.
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors.forename: Chunlan
authors.initials: C
authors.lastname: Hua
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors.forename: Huidong
authors.initials: H
authors.lastname: Guo
authors.affiliation: Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Jiachen
authors.initials: J
authors.lastname: Bu
authors.affiliation: Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Mi
authors.initials: M
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Fuhong
authors.initials: F
authors.lastname: He
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors.forename: Jinhong
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors.forename: Yinchi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Qianfei
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Cheng
authors.affiliation: Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Mingjiang
authors.initials: M
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China. Electronic address: wpyuan@ihcams.ac.cn.
authors.forename: Weiping
authors.initials: W
authors.lastname: Yuan
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic; D002633:Chemotaxis / Q000235:genetics; D018450:Disease Progression; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000502:physiology*; D015973:Gene Expression Regulation, Leukemic; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000502:physiology*; D009363:Neoplasm Proteins / Q000502:physiology*; D009928:Organ Specificity; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D011828:Radiation Chimera; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D051881:Receptor, Notch1 / Q000502:physiology*; D016192:Resting Phase, Cell Cycle; D013154:Spleen / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; C497762:Notch1 protein, mouse; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D051881:Receptor, Notch1; C525637:rictor protein, mouse; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases