title: Rictor has a pivotal role in maintaining quiescence as well as stemness of leukemia stem cells in MLL-driven leukemia.
abstract: Little is known about the roles of Rictor/mTORC2 in the leukemogenesis of acute myeloid leukemia. Here, we demonstrated that Rictor is essential for the maintenance of mixed lineage leukemia (MLL)-driven leukemia by preventing leukemia stem cells (LSCs) from exhaustion. Rictor depletion led to a reactive activation of mTORC1 signaling by facilitating the assembly of mTORC1. Hyperactivated mTORC1 signaling in turn drove LSCs into cycling, compromised the quiescence of LSCs and eventually exhausted their capacity to generate leukemia. At the same time, loss of Rictor had led to a reactive activation of FoxO3a in leukemia cells, which acts as negative feedback to restrain greater over-reactivation of mTORC1 activity and paradoxically protects leukemia cells from exhaustion. Simultaneous depletion of Rictor and FoxO3a enabled rapid exhaustion of MLL LSCs and a quick eradication of MLL leukemia. As such, our present findings highlighted a pivotal regulatory axis of Rictor-FoxO3a in maintaining quiescence and the stemness of LSCs.
authors: Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.|Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors: Y
authors: Y
authors: Fang
authors: Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.|Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors: Y
authors: Y
authors: Yang
authors: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors: C
authors: C
authors: Hua
authors: Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.|Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors: S
authors: S
authors: Xu
authors: Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.|Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors: M
authors: M
authors: Zhou
authors: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors: H
authors: H
authors: Guo
authors: Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.|Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors: N
authors: N
authors: Wang
authors: Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors: X
authors: X
authors: Zhao
authors: Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.|Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors: L
authors: L
authors: Huang
authors: Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.|Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors: F
authors: F
authors: Yu
authors: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors: H
authors: H
authors: Cheng
authors: Department of Lymphoma/ Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: M L
authors: ML
authors: Wang
authors: Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.|Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors: L
authors: L
authors: Meng
authors: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors: T
authors: T
authors: Cheng
authors: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors: W
authors: 0000-0001-8288-5022
authors: W
authors: Yuan
authors: Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors: D
authors: D
authors: Ma
authors: Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.|Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors: J
authors: J
authors: Zhou
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D000066673:Cell Self Renewal / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic; D016000:Cluster Analysis; D000071316:Forkhead Box Protein O3 / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D016192:Resting Phase, Cell Cycle / Q000235:genetics*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D000071316:Forkhead Box Protein O3; D046912:Multiprotein Complexes; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C525637:rictor protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases