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Loss of Folliculin Disrupts Hematopoietic Stem Cell Quiescence and Homeostasis Resulting in Bone Marrow Failure.
Baba, Masaya; Toyama, Hirofumi; Sun, Lei; Takubo, Keiyo; Suh, Hyung-Chan; Hasumi, Hisashi; Nakamura-Ishizu, Ayako; Hasumi, Yukiko; Klarmann, Kimberly D; Nakagata, Naomi; Schmidt, Laura S; Linehan, W Marston; Suda, Toshio; Keller, Jonathan R.
Afiliación
  • Baba M; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
  • Toyama H; International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan.
  • Sun L; Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo, Japan.
  • Takubo K; Mouse Cancer Genetics Program, Frederick, Maryland, USA.
  • Suh HC; Basic Science Program, Leidos Biomedical Research, Inc., Center for Cancer Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
  • Hasumi H; Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo, Japan.
  • Nakamura-Ishizu A; Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
  • Hasumi Y; Mouse Cancer Genetics Program, Frederick, Maryland, USA.
  • Klarmann KD; Basic Science Program, Leidos Biomedical Research, Inc., Center for Cancer Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
  • Nakagata N; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
  • Schmidt LS; Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo, Japan.
  • Linehan WM; Cancer Science Institute (CSI), National University of Singapore (NUS), Singapore.
  • Suda T; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
  • Keller JR; Mouse Cancer Genetics Program, Frederick, Maryland, USA.
Stem Cells ; 34(4): 1068-82, 2016 Apr.
Article en En | MEDLINE | ID: mdl-27095138
Folliculin (FLCN) is an autosomal dominant tumor suppressor gene that modulates diverse signaling pathways required for growth, proliferation, metabolism, survival, motility, and adhesion. FLCN is an essential protein required for murine embryonic development, embryonic stem cell (ESC) commitment, and Drosophila germline stem cell maintenance, suggesting that Flcn may be required for adult stem cell homeostasis. Conditional inactivation of Flcn in adult hematopoietic stem/progenitor cells (HSPCs) drives hematopoietic stem cells (HSC) into proliferative exhaustion resulting in the rapid depletion of HSPC, loss of all hematopoietic cell lineages, acute bone marrow (BM) failure, and mortality after 40 days. HSC that lack Flcn fail to reconstitute the hematopoietic compartment in recipient mice, demonstrating a cell-autonomous requirement for Flcn in HSC maintenance. BM cells showed increased phosphorylation of Akt and mTorc1, and extramedullary hematopoiesis was significantly reduced by treating mice with rapamycin in vivo, suggesting that the mTorc1 pathway was activated by loss of Flcn expression in hematopoietic cells in vivo. Tfe3 was activated and preferentially localized to the nucleus of Flcn knockout (KO) HSPCs. Tfe3 overexpression in HSPCs impaired long-term hematopoietic reconstitution in vivo, recapitulating the Flcn KO phenotype, and supporting the notion that abnormal activation of Tfe3 contributes to the Flcn KO phenotype. Flcn KO mice develop an acute histiocytic hyperplasia in multiple organs, suggesting a novel function for Flcn in macrophage development. Thus, Flcn is intrinsically required to maintain adult HSC quiescence and homeostasis, and Flcn loss leads to BM failure and mortality in mice.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre Hematopoyéticas / Diferenciación Celular / Estrona / Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice Límite: Animals Idioma: En Revista: Stem Cells Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células Madre Hematopoyéticas / Diferenciación Celular / Estrona / Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice Límite: Animals Idioma: En Revista: Stem Cells Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido