Loss of Folliculin Disrupts Hematopoietic Stem Cell Quiescence and Homeostasis Resulting in Bone Marrow Failure.
Loss of Folliculin Disrupts Hematopoietic Stem Cell Quiescence and Homeostasis Resulting in Bone Marrow Failure.
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DOI：
10.1002/stem.2293
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发表时间：
2016-04
期刊：
影响因子：
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通讯作者：
Keller JR
中科院分区：
文献类型：
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作者：
Baba M;Toyama H;Sun L;Takubo K;Suh HC;Hasumi H;Nakamura-Ishizu A;Hasumi Y;Klarmann KD;Nakagata N;Schmidt LS;Linehan WM;Suda T;Keller JR
卵泡蛋白是一种常染色体显性肿瘤抑制基因，调控多种信号通路，参与肿瘤的生长、增殖、代谢、存活、运动和黏附。Flcn是小鼠胚胎发育、胚胎干细胞(ESC)承诺和果蝇生殖系干细胞维持所必需的蛋白质，提示Flcn可能是成体干细胞动态平衡所必需的。成体造血干/祖细胞(HSPC)中Flcn的条件失活可使HSC进入增殖性衰竭状态，导致HSPC迅速耗尽，所有造血细胞谱系丧失，急性骨髓衰竭，40天后死亡。缺乏Flcn的HSC不能重建受体小鼠的造血室，表明Flcn在HSC维持中是一种细胞自主的需求。体内用雷帕霉素处理的小鼠骨髓细胞(BMC)Akt和mTORC1的磷酸化水平升高，髓外造血明显减少，提示体内造血细胞中FlcN的表达缺失激活了mTORC1途径。TFE3被激活，并优先定位于FLCN基因敲除(KO)HSPC的胞核。TFE3在HSPC中的过表达损害了体内长期的造血重建，概括了FLCN KO的表型，并支持TFE3的异常激活与FLCN KO表型有关的观点。Flcn KO小鼠在多个器官出现急性组织细胞增生，提示了Flcn在巨噬细胞发育中的新功能。因此，Flcn是维持成人HSC静止和动态平衡的内在要求，而Flcn的缺失会导致小鼠的骨髓衰竭和死亡。
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 HSC into proliferative exhaustion resulting in the rapid depletion of HSPC, loss of all hematopoietic cell lineages, acute bone marrow 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. Bone marrow cells (BMC) 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 bone marrow failure and mortality in mice.