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Hematopoiesis
Rheb1 loss leads to increased hematopoietic stem cell proliferation and myeloid-biased differentiation in vivo
Ferrata Storti Foundation
Xiaomin Wang,1* Yanan Gao,1* Juan Gao,1* Minghao Li,1 Mi Zhou,2
Jinhong Wang,1 Yakun Pang,1 Hui Cheng,1 Chase Yuan,3 Yajing Chu,1 Yu Jiang,4 Jianfeng Zhou,2 Hongbo R. Luo,1,5 Zhenyu Ju,6 Tao Cheng1 and Weiping Yuan1
1State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China; 2Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; 3College of Arts and Sciences, University of North Carolina at Chapel Hill, NC, USA; 4Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; 5Department of Pathology, Harvard Medical School, Dana-Farber/Harvard Cancer Center, Boston, MA, USA and 6Institute of Aging, Hangzhou Normal University, Hangzhou, China
Haematologica 2019 Volume 104(2):245-255
*XM, YG and JG contributed equally to this work.
ABSTRACT
Hematopoietic stem cells constitute a unique subpopulation of blood cells that can give rise to all types of mature cells in response to physiological demands. However, the intrinsic molecular machinery that regulates this transformative property remains elusive. In this paper, we demonstrate that small GTPase Rheb1 is a crit- ical regulator of proliferation and differentiation of hematopoietic stem cells in vivo. Rheb1 deletion led to increased phenotypic hematopoietic stem cell/hematopoietic progenitor cell proliferation under a steady state condition. Over-proliferating Rheb1-deficient hematopoietic stem cells were severely impaired in functional repopulation assays, and they failed to regenerate the blood system when challenged with hematopoietic ablation by sublethal irradiation. In addition, it was discovered that Rheb1 loss resulted in a lack of maturation of neutrophils / caused neu- trophil immaturation by reducing mTORC1 activity, and that activation of the mTORC1 signaling pathway by mTOR activator 3BDO partially restored the maturation of Rheb1-deficient neutrophils. Rheb1 deficien- cy led to a progressive enlargement of the hematopoietic stem cell pop- ulation and an eventual excessive myeloproliferation in vivo, including an overproduction of peripheral neutrophils and an excessive expansion of extramedullary hematopoiesis. Moreover, low RHEB expression was correlated with poor survival in acute myeloid leukemia patients with normal karyotype. Our results, therefore, demonstrate a critical and unique role for Rheb1 in maintaining proper hematopoiesis and myeloid differentiation.
Introduction
Hematopoietic stem cell (HSC) proliferation and differentiation are regulated by the networks of signaling pathways.1 Under stress conditions, HSCs quickly respond to a variety of proliferative stimuli, exit the quiescent phase, and undergo a period of self-renewal and differentiation to restore hematopoietic homeostasis.2 Fine-tuning is required to adequately control cell growth and quiescence during this process, and multiple signaling pathways are involved in maintaining the correct balance. Interestingly, studies have suggested that common or similar mechanisms regulate stem cell properties in both HSCs and leukemia stem cells (LSCs), suggest- ing that LSCs may originate from HSCs. The mammalian target of the rapamycin (mTOR) signaling pathway is a key node in these pathways, and plays an essential role in regulating normal and malignant hematopoiesis.3,4
Ras homolog enriched in brain (Rheb), a small GTPase, is known to directly acti-
Correspondence:
wpyuan@ihcams.ac.cn or chengtao@ihcams.ac.cn or zhenyuju@163.com
Received: April 7, 2018.
Accepted: September 21, 2018. Pre-published: September 27, 2018.
doi:10.3324/haematol.2018.194811
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/2/245
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