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Rheb1 loss leads to increased hematopoietic stem cell proliferation and myeloid-biased differentiation in vivo.

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 critical 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 neutrophil 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 deficiency led to a progressive enlargement of the hematopoietic stem cell population 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.

SUBMITTER: Wang X

PROVIDER: S-EPMC6355497 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Rheb1 loss leads to increased hematopoietic stem cell proliferation and myeloid-biased differentiation <i>in vivo</i>.

Wang Xiaomin X Gao Yanan Y Gao Juan J Li Minghao M Zhou Mi M Wang Jinhong J Pang Yakun Y Cheng Hui H Yuan Chase C Chu Yajing Y Jiang Yu Y Zhou Jianfeng J Luo Hongbo R HR Ju Zhenyu Z Cheng Tao T Yuan Weiping W

Haematologica 20180927 2

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 critical regulator of proliferation and differentiation of hematopoietic stem cells <i>in vivo</i> Rheb1 deletion led to increased phenotypic hematopoietic stem cell/hematopoiet ...[more]

PMID: 30262562

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Project description:The genesp53, mdm2, p21, c-myc,bcr/abl, bcr, bcl2, bax, and gapdh participate in the regulation of cell proliferation and differentiation, apoptosis and cell distribution for the cell cycle ex vivo in the Ph(+)cells of chronic myeloid leukemia containing the Ph chromosome andbcr/abloncogene. Expression of these genes correlates with regulation of cell proliferation and differentiation by alternating proliferation and maturation stages for three main Ph+cell types that occur under chronic myeloid leukemia. Thep53, p21, mdm2, and gapdh genes overexpress in active proliferating myeloid cells in the cell cycle S+ G2/M phases and when the phases are coincident with the proliferation stage. Expression of these genes decreases to a considerable level under alternation of the Ph(+)cell proliferation and maturation stages and whenever the expression is greatly diminished under significant neutrophil accumulation and especially under repeated alternation of the stages. In the course of neutrophil maturation, gene expression levels decrease in the range of gapdh > actin > c-myc, bcr/abl,p21 > p53 > bcl2 > bax.The expression levels of these genes in neutrophils are lower than those in myelocytes and lower by an order of magnitude than that in the cells with a prolonged proliferation stage. TheBcr/ablexpression gene under prolonged maturation and neutrophil accumulation is inhibited; however it is enhanced by 2-3 times for the proliferation stage with myelocyte accumulation. Minimalbcr/ablexpression is observed under overexpression ofp53, mdm2, p21, c-myc,as well as under cell maximum at the S and G2/M phases. Bcr/abloverexpression is observed under low expression of thep53, p21, mdm2genes. In the Ph(+ )cells with a high P/D efficiency index (5-20), overexpression of the genes in the range ofbcr> gapdh>bcr/abl, as well as a decreased expression of thep53, bcl2, mdm2, p21<< gapdh genes is observed for Ph(+)cells from the CML blast crisis and CML acceleration phase. Low control of cell proliferation and cell cycle by gene-regulators presumably promotesbcr/abloverexpression and activ?tes the production ofbcr/abl+ cells. Apoptosis in the Ph(+ )cells is induced by expression of thebax > bcl2, ?53, p21, c-myc andgapdhgenes. The blocking of Ph(+)cell apoptosis, neutrophil accumulation, and decrease in the expression of the p53, mdm2 and p21, c-myc,bcr/abl genes occur at the maturation stage.

Dataset Information

Rheb1 loss leads to increased hematopoietic stem cell proliferation and myeloid-biased differentiation in vivo.

Publications

Rheb1 loss leads to increased hematopoietic stem cell proliferation and myeloid-biased differentiation <i>in vivo</i>.

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