Loss of Folliculin Disrupts Hematopoietic Stem Cell Quiescence and Homeostasis Resulting in Bone Marrow Failure.
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.
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.|International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan.
Masaya
M
Baba
Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo, Japan.
Hirofumi
H
Toyama
Mouse Cancer Genetics Program, Frederick, Maryland, USA.|Basic Science Program, Leidos Biomedical Research, Inc., Center for Cancer Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
Lei
L
Sun
Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo, Japan.|Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
Keiyo
K
Takubo
Mouse Cancer Genetics Program, Frederick, Maryland, USA.|Basic Science Program, Leidos Biomedical Research, Inc., Center for Cancer Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
Hyung-Chan
HC
Suh
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Hisashi
H
Hasumi
Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo, Japan.|Cancer Science Institute (CSI), National University of Singapore (NUS), Singapore.
Ayako
A
Nakamura-Ishizu
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Yukiko
Y
Hasumi
Mouse Cancer Genetics Program, Frederick, Maryland, USA.|Basic Science Program, Leidos Biomedical Research, Inc., Center for Cancer Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
Kimberly D
KD
Klarmann
Division of Reproductive Engineering, Center for Animal Resources and Development (CARD), Kumamoto University, Kumamoto, Japan.
Naomi
N
Nakagata
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.|Basic Science Program, Leidos Biomedical Research, Inc., Center for Cancer Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
Laura S
LS
Schmidt
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
W Marston
WM
Linehan
International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan.|Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo, Japan.|Cancer Science Institute (CSI), National University of Singapore (NUS), Singapore.
Toshio
T
Suda
Mouse Cancer Genetics Program, Frederick, Maryland, USA.|Basic Science Program, Leidos Biomedical Research, Inc., Center for Cancer Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
Jonathan R
JR
Keller
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D001854:Bone Marrow Cells / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D047108:Embryonic Development / Q000235:genetics; D004970:Estrone / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D006706:Homeostasis / Q000235:genetics; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C068486:Tcfe3 protein, mouse; D004970:Estrone
Bone marrow failure; Folliculin; Hematopoiesis; Stem cells