mTORC signaling in hematopoiesis

Wang, Xiaomin; Chu, Yajing; Wang, Weili; Yuan, Weiping

doi:10.1007/s12185-016-1944-z

Cited by 29 publications

(19 citation statements)

References 98 publications

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“…We tested several drugs and cytokines that regulate cell signaling to investigate the mechanism of MEP fate determination, including 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) ( Ho et al, 2017 ) (an analog of AMP), mitochondrially targeted antioxidant (mitoTEMPO) ( Jang et al, 2015 ), interleukin-9 (IL-9), IL-11, Ly364947( Naka et al, 2010 ) (a transforming growth factor β [TGF-β] inhibitor), all- trans retinoic acid (ATRA), and rapamycin ( Wang et al, 2016 ) (a mechanistic target of rapamycin [mTOR] inhibitor). However, only Ly364947, ATRA, and rapamycin affected the MEP fate decision ( Figure 5 ); the others had no significant effect (data not shown).…”

Section: Resultsmentioning

confidence: 99%

The Molecular Signature of Megakaryocyte-Erythroid Progenitors Reveals a Role for the Cell Cycle in Fate Specification

Sanada

Xavier-Ferrucio

et al. 2018

Cell Reports

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SUMMARY Megakaryocytic-erythroid progenitors (MEPs) give rise to the cells that produce red blood cells and platelets. Although the mechanisms underlying megakaryocytic (MK) and erythroid (E) maturation have been described, those controlling their specification from MEPs are unknown. Single-cell RNA sequencing of primary human MEPs, common myeloid progenitors (CMPs), megakaryocyte progenitors, and E progenitors revealed a distinct transitional MEP signature. Inferred regulatory transcription factors (TFs) were associated with differential expression of cell cycle regulators. Genetic manipulation of selected TFs validated their role in lineage specification and demonstrated coincident modulation of the cell cycle. Genetic and pharmacologic modulation demonstrated that cell cycle activation is sufficient to promote E versus MK specification. These findings, obtained from healthy human cells, lay a foundation to study the mechanisms underlying benign and malignant disease states of the megakaryocytic and E lineages.

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Section: Resultsmentioning

confidence: 99%

The Molecular Signature of Megakaryocyte-Erythroid Progenitors Reveals a Role for the Cell Cycle in Fate Specification

Sanada

Xavier-Ferrucio

et al. 2018

Cell Reports

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“…Using naturally-aged wild type mice and genetically-modified premature ageing mouse models [8] , [9] , [10] , [11] , [12] , [13] , intrinsic and extrinsic factors contributing to the HSC ageing start to be unraveled [4] , [14] , [15] , [16] . Among them, cell cycle regulators, transcriptional factors, epigenetic modulators, and metabolic pathways have been implicated as important regulators for HSC self-renewal and maintenance during ageing process [10] , [12] , [17] , [18] , [19] , [20] , [21] , [22] , [23] .…”

Section: Introductionmentioning

confidence: 99%

DNA Damage Response in Hematopoietic Stem Cell Ageing

Zhou

et al. 2016

Genomics, Proteomics &Amp; Bioinformatics

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Maintenance of tissue-specific stem cells is vital for organ homeostasis and organismal longevity. Hematopoietic stem cells (HSCs) are the most primitive cell type in the hematopoietic system. They divide asymmetrically and give rise to daughter cells with HSC identity (self-renewal) and progenitor progenies (differentiation), which further proliferate and differentiate into full hematopoietic lineages. Mammalian ageing process is accompanied with abnormalities in the HSC self-renewal and differentiation. Transcriptional changes and epigenetic modulations have been implicated as the key regulators in HSC ageing process. The DNA damage response (DDR) in the cells involves an orchestrated signaling pathway, consisting of cell cycle regulation, cell death and senescence, transcriptional regulation, as well as chromatin remodeling. Recent studies employing DNA repair-deficient mouse models indicate that DDR could intrinsically and extrinsically regulate HSC maintenance and play important roles in tissue homeostasis of the hematopoietic system. In this review, we summarize the current understanding of how the DDR determines the HSC fates and finally contributes to organismal ageing.

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“…mTOR interacts with multi-proteins to form two distinct complexes, designated mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Raptor and PRAS40 belong specifically to mTORC1, while Rictor, mSin1 and Protor are specific components of mTORC2 (56,57). mTOR complexes play critical roles in both normal hematopoiesis and leukemogenesis (58,59).…”

Section: Tsc Complex and Rhebmentioning

confidence: 99%

Will targeting PI3K/Akt/mTOR signaling work in hematopoietic malignancies?

Gao

Yuan²,

Yuan

2016

Stem Cell Investig.

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Abstract:The constitutive activation of phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway has been demonstrated to be critical in clinical cancer patients as well as in laboratory cancer models including hematological malignancies. Great efforts have been made to develop inhibitors targeting this pathway in hematological malignancies but so far the efficacies of these inhibitors were not as good as expected. By analyzing existing literatures and datasets available, we found that mutations of genes in the pathway only constitute a very small subset of hematological malignancies. Deep understanding of the function of gene, the pathway and/or its regulators, and the cellular response to inhibitors, may help us design better drugs targeting the hematological malignancies.

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mTORC signaling in hematopoiesis

Cited by 29 publications

References 98 publications

The Molecular Signature of Megakaryocyte-Erythroid Progenitors Reveals a Role for the Cell Cycle in Fate Specification

The Molecular Signature of Megakaryocyte-Erythroid Progenitors Reveals a Role for the Cell Cycle in Fate Specification

DNA Damage Response in Hematopoietic Stem Cell Ageing

Will targeting PI3K/Akt/mTOR signaling work in hematopoietic malignancies?

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