PMID- 33443202 OWN - NLM STAT- MEDLINE DCOM- 20210430 LR - 20211204 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 118 IP - 1 DP - 2021 Jan 5 TI - Adaptive responses to mTOR gene targeting in hematopoietic stem cells reveal a proliferative mechanism evasive to mTOR inhibition. LID - 10.1073/pnas.2020102118 [doi] LID - e2020102118 AB - The mechanistic target of rapamycin (mTOR) is a central regulator of cell growth and an attractive anticancer target that integrates diverse signals to control cell proliferation. Previous studies using mTOR inhibitors have shown that mTOR targeting suppresses gene expression and cell proliferation. To date, however, mTOR-targeted therapies in cancer have seen limited efficacy, and one key issue is related to the development of evasive resistance. In this manuscript, through the use of a gene targeting mouse model, we have found that inducible deletion of mTOR in hematopoietic stem cells (HSCs) results in a loss of quiescence and increased proliferation. Adaptive to the mTOR loss, mTOR(-/-) HSCs increase chromatin accessibility and activate global gene expression, contrary to the effects of short-term inhibition by mTOR inhibitors. Mechanistically, such genomic changes are due to a rewiring and adaptive activation of the ERK/MNK/eIF4E signaling pathway that enhances the protein translation of RNA polymerase II, which in turn leads to increased c-Myc gene expression, allowing the HSCs to thrive despite the loss of a functional mTOR pathway. This adaptive mechanism can also be utilized by leukemia cells undergoing long-term mTOR inhibitor treatment to confer resistance to mTOR drug targeting. The resistance can be counteracted by MNK, CDK9, or c-Myc inhibition. These results provide insights into the physiological role of mTOR in mammalian stem cell regulation and implicate a mechanism of evasive resistance in the context of mTOR targeting. FAU - Fan, Cuiqing AU - Fan C AD - Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229. AD - Institute of Pediatrics, Children's Hospital of Fudan University, 201102 Shanghai, China. FAU - Zhao, Chuntao AU - Zhao C AUID- ORCID: 0000-0002-2226-3827 AD - Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229. FAU - Zhang, Feng AU - Zhang F AD - Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229. FAU - Kesarwani, Meenu AU - Kesarwani M AUID- ORCID: 0000-0003-3925-3809 AD - Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229. AD - Division of Pathology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229. FAU - Tu, Zhaowei AU - Tu Z AUID- ORCID: 0000-0001-6070-8447 AD - Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229. FAU - Cai, Xiongwei AU - Cai X AD - Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229. FAU - Davis, Ashley Kuenzi AU - Davis AK AUID- ORCID: 0000-0003-1162-3994 AD - Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229. FAU - Xu, Lingli AU - Xu L AD - Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229. FAU - Hochstetler, Cindy L AU - Hochstetler CL AD - Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229. FAU - Chen, Xiaoyi AU - Chen X AD - Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229. FAU - Guo, Fukun AU - Guo F AD - Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229. FAU - Huang, Gang AU - Huang G AD - Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229. AD - Division of Pathology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229. FAU - Azam, Mohammad AU - Azam M AUID- ORCID: 0000-0002-3019-2221 AD - Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229. AD - Division of Pathology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229. FAU - Tian, Weidong AU - Tian W AD - Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229. FAU - Lu, Q Richard AU - Lu QR AUID- ORCID: 0000-0001-6846-9014 AD - Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229. FAU - Zheng, Yi AU - Zheng Y AD - Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; yi.zheng@cchmc.org. LA - eng GR - R01 CA155091/CA/NCI NIH HHS/United States GR - R01 CA211594/CA/NCI NIH HHS/United States GR - R01 CA250516/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20201221 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Chromatin) RN - 0 (Eukaryotic Initiation Factor-4E) RN - 0 (Protein Kinase Inhibitors) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.22 (Cyclin-Dependent Kinase 9) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) RN - EC 2.7.7.- (RNA Polymerase II) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Animals MH - Cell Cycle/drug effects MH - Cell Line, Tumor MH - Cell Proliferation/*drug effects/genetics MH - Chromatin/metabolism MH - Chromatin Immunoprecipitation Sequencing MH - Cyclin-Dependent Kinase 9/metabolism MH - Eukaryotic Initiation Factor-4E/metabolism MH - Extracellular Signal-Regulated MAP Kinases/metabolism MH - Gene Targeting MH - Genes, myc/genetics MH - Hematopoietic Stem Cells/*metabolism MH - MAP Kinase Signaling System/drug effects/genetics MH - Mice MH - Mice, Knockout MH - Phosphorylation/drug effects MH - Protein Kinase Inhibitors/pharmacology MH - RNA Polymerase II/metabolism MH - Sirolimus/*pharmacology MH - TOR Serine-Threonine Kinases/*antagonists & inhibitors/*genetics/metabolism PMC - PMC7817152 OTO - NOTNLM OT - adaptive compensation OT - drug resistance OT - hematopoietic stem cells OT - leukemia OT - mTOR COIS- The authors declare no competing interest. EDAT- 2021/01/15 06:00 MHDA- 2021/05/01 06:00 PMCR- 2021/06/28 CRDT- 2021/01/14 08:50 PHST- 2021/01/14 08:50 [entrez] PHST- 2021/01/15 06:00 [pubmed] PHST- 2021/05/01 06:00 [medline] PHST- 2021/06/28 00:00 [pmc-release] AID - 2020102118 [pii] AID - 202020102 [pii] AID - 10.1073/pnas.2020102118 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2021 Jan 5;118(1):e2020102118. doi: 10.1073/pnas.2020102118. Epub 2020 Dec 21.