PMID- 27071307 OWN - NLM STAT- MEDLINE DCOM- 20161017 LR - 20211203 IS - 1756-8722 (Electronic) IS - 1756-8722 (Linking) VI - 9 DP - 2016 Apr 12 TI - Rheb1 promotes tumor progression through mTORC1 in MLL-AF9-initiated murine acute myeloid leukemia. PG - 36 LID - 10.1186/s13045-016-0264-3 [doi] LID - 36 AB - BACKGROUND: The constitutive hyper-activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathways has frequently been associated with acute myeloid leukemia (AML). While many inhibitors targeting these pathways have been developed, the anti-leukemic effect was not as robust as expected. As part of the molecular link between PI3K/Akt and mTOR kinase, the role of Rheb1 in AML remains unexplored. Our study aims to explore the role of Rheb1 in AML and estimate whether Rheb1 could be a potential target of AML treatment. METHODS: The expressions of Rheb1 and other indicated genes were analyzed using real-time PCR. AML mouse model was established by retrovirus transduction. Leukemia cell properties and related signaling pathways were dissected by in vitro and in vivo studies. The transcriptional changes were analyzed via gene chip analysis. Molecular reagents including mTOR inhibitor and mTOR activator were used to evaluate the function of related signaling pathway in the mouse model. RESULTS: We observed that Rheb1 is overexpressed in AML patients and the change of Rheb1 level in AML patients is associated with their median survival. Using a Rheb1-deficient MLL-AF9 murine AML model, we revealed that Rheb1 deletion prolonged the survival of AML mice by weakening LSC function. In addition, Rheb1 deletion arrested cell cycle progression and enhanced apoptosis of AML cells. Furthermore, while Rheb1 deletion reduced mTORC1 activity in AML cells, additional rapamycin treatment further decreased mTORC1 activity and increased the apoptosis of Rheb1 (Delta/Delta) AML cells. The mTOR activator 3BDO partially rescued mTORC1 signaling and inhibited apoptosis in Rheb1 (Delta/Delta) AML cells. CONCLUSIONS: Our data suggest that Rheb1 promotes AML progression through mTORC1 signaling pathway and combinational drug treatments targeting Rheb1 and mTOR might have a better therapeutic effect on leukemia. FAU - Gao, Yanan AU - Gao Y AD - State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, CAMS & PUMC, Beijing, China. FAU - Gao, Juan AU - Gao J AD - State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, CAMS & PUMC, Beijing, China. FAU - Li, Minghao AU - Li M AD - State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, CAMS & PUMC, Beijing, China. FAU - Zheng, Yawei AU - Zheng Y AD - State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, CAMS & PUMC, Beijing, China. FAU - Wang, Yajie AU - Wang Y AD - State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, CAMS & PUMC, Beijing, China. FAU - Zhang, Hongyan AU - Zhang H AD - State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, CAMS & PUMC, Beijing, China. FAU - Wang, Weili AU - Wang W AD - State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, CAMS & PUMC, Beijing, China. FAU - Chu, Yajing AU - Chu Y AD - State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, CAMS & PUMC, Beijing, China. FAU - Wang, Xiaomin AU - Wang X AD - State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, CAMS & PUMC, Beijing, China. xminwang@hotmail.com. FAU - Xu, Mingjiang AU - Xu M AD - Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, USA. FAU - Cheng, Tao AU - Cheng T AD - State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, CAMS & PUMC, Beijing, China. FAU - Ju, Zhenyu AU - Ju Z AD - Institute of Aging, Hangzhou Normal University, Hangzhou, 310036, China. FAU - Yuan, Weiping AU - Yuan W AD - State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, CAMS & PUMC, Beijing, China. wpyuan@ihcams.ac.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160412 PL - England TA - J Hematol Oncol JT - Journal of hematology & oncology JID - 101468937 RN - 0 (Antibiotics, Antineoplastic) RN - 0 (MLL-AF9 fusion protein, mouse) RN - 0 (Multiprotein Complexes) RN - 0 (Neuropeptides) RN - 0 (Oncogene Proteins, Fusion) RN - 0 (Ras Homolog Enriched in Brain Protein) RN - 0 (Rheb protein, mouse) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.6.5.2 (Monomeric GTP-Binding Proteins) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Acute Disease MH - Animals MH - Antibiotics, Antineoplastic/pharmacology MH - Apoptosis/drug effects/genetics MH - Blotting, Western MH - Cell Cycle Checkpoints/drug effects/genetics MH - Cells, Cultured MH - Disease Models, Animal MH - Gene Expression Regulation, Leukemic MH - Humans MH - Kaplan-Meier Estimate MH - Leukemia, Myeloid/*genetics/metabolism/pathology MH - Mechanistic Target of Rapamycin Complex 1 MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Monomeric GTP-Binding Proteins/*genetics/metabolism MH - Multiprotein Complexes/*genetics/metabolism MH - Neuropeptides/*genetics/metabolism MH - Oncogene Proteins, Fusion/*genetics/metabolism MH - Ras Homolog Enriched in Brain Protein MH - Reverse Transcriptase Polymerase Chain Reaction MH - Signal Transduction/drug effects/genetics MH - Sirolimus/pharmacology MH - TOR Serine-Threonine Kinases/*genetics/metabolism PMC - PMC4830070 OTO - NOTNLM OT - 3BDO OT - Leukemia OT - MLL-AF9 OT - Rapamycin OT - Rheb1 OT - mTORC1 EDAT- 2016/04/14 06:00 MHDA- 2016/10/19 06:00 PMCR- 2016/04/12 CRDT- 2016/04/14 06:00 PHST- 2016/01/15 00:00 [received] PHST- 2016/04/03 00:00 [accepted] PHST- 2016/04/14 06:00 [entrez] PHST- 2016/04/14 06:00 [pubmed] PHST- 2016/10/19 06:00 [medline] PHST- 2016/04/12 00:00 [pmc-release] AID - 10.1186/s13045-016-0264-3 [pii] AID - 264 [pii] AID - 10.1186/s13045-016-0264-3 [doi] PST - epublish SO - J Hematol Oncol. 2016 Apr 12;9:36. doi: 10.1186/s13045-016-0264-3.