title: Rictor is required for early B cell development in bone marrow.
abstract: The development of early B cells, which are generated from hematopoietic stem cells (HSCs) in a series of well-characterized stages in bone marrow (BM), represents a paradigm for terminal differentiation processes. Akt is primarily regulated by phosphorylation at Thr308 by PDK1 and at Ser473 by mTORC2, and Akt signaling plays a key role in hematopoiesis. However, the role of mTORC2 in the development of early B cells remains poorly understood. In this study, we investigated the functional role of mTORC2 by specifically deleting an integral component, Rictor, in a hematopoietic system. We demonstrated that the deletion of Rictor induced an aberrant increase in the FoxO1 and Rag-1 proteins in BM B cells and that this increase was accompanied by a significant decrease in the abundance of B cells in the peripheral blood (PB) and the spleen, suggesting impaired development of early B cells in adult mouse BM. A BM transplantation assay revealed that the B cell differentiation defect induced by Rictor deletion was not affected by the BM microenvironment, thus indicating a cell-intrinsic mechanism. Furthermore, the knockdown of FoxO1 in Rictor-deleted HSCs and hematopoietic progenitor cells (HPCs) promoted the maturation of B cells in the BM of recipient mice. In addition, we revealed that treatment with rapamycin (an mTORC1 inhibitor) aggravated the deficiency in B cell development in the PB and BM. Taken together, our results provide further evidence that Rictor regulates the development of early B cells in a cell-intrinsic manner by modifying the expression of FoxO1 and Rag-1.
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Yingchi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Tianyuan
authors.initials: T
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Beijing, 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, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Gu
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Liyan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Sha
authors.initials: S
authors.lastname: Hao
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Haoyue
authors.initials: H
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Beijing, 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, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Weili
authors.initials: W
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Hanzhi
authors.initials: H
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; 307-Ivy Translational Medicine Center, Laboratory of Oncology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Weiping
authors.initials: W
authors.lastname: Yuan
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D001773:Blood Cells / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D020123:Sirolimus / Q000494:pharmacology; D013154:Spleen / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D018398:Homeodomain Proteins; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C525637:rictor protein, mouse; C064658:RAG-1 protein; D020123:Sirolimus
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