气候变化领域集成服务门户(CCPortal): Tuning MPL signaling to influence hematopoietic stem cell differentiation and inhibit essential thrombocythemia progenitors

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DOI	10.1073/pnas.2017849118
	Tuning MPL signaling to influence hematopoietic stem cell differentiation and inhibit essential thrombocythemia progenitors
	Cui L.; Moraga I.; Lerbs T.; van Neste C.; Wilmes S.; Tsutsumi N.; Trotman-Grant A.C.; Gakovic M.; Andrews S.; Gotlib J.; Darmanis S.; Enge M.; Quake S.; Hitchcock I.S.; Piehler J.; Christopher Garcia K.; Wernig G.
发表日期	2021
ISSN	00278424
卷号	118 期号:2
英文摘要	Thrombopoietin (TPO) and the TPO-receptor (TPO-R, or c-MPL) are essential for hematopoietic stem cell (HSC) maintenance and megakaryocyte differentiation. Agents that can modulate TPO-R signaling are highly desirable for both basic research and clinical utility. We developed a series of surrogate protein ligands for TPO-R, in the form of diabodies (DBs), that homodimerize TPO-R on the cell surface in geometries that are dictated by the DB receptor binding epitope, in effect “tuning” downstream signaling responses. These surrogate ligands exhibit diverse pharmacological properties, inducing graded signaling outputs, from full to partial TPO agonism, thus decoupling the dual functions of TPO/TPO-R. Using single-cell RNA sequencing and HSC self-renewal assays we find that partial agonistic diabodies preserved the stem-like properties of cultured HSCs, but also blocked oncogenic colony formation in essential thrombocythemia (ET) through inverse agonism. Our data suggest that dampening downstream TPO signaling is a powerful approach not only for HSC preservation in culture, but also for inhibiting oncogenic signaling through the TPO-R. © This open access article is distributed under Creative Commons Attribution-NonCommercialNoDerivatives License 4.0 (CC BY-NC-ND).
英文关键词	Hematopoietic stem cells; Megakaryopoiesis; Myeloproliferative neoplasm; Thrombopoietin signaling
语种	英语
scopus关键词	Janus kinase 2; mitogen activated protein kinase p38; Myc protein; phosphatidylinositol 3 kinase; protein Bax; protein p53; RNA; single cell RNA; single chain fragment variable antibody; STAT1 protein; STAT3 protein; STAT5 protein; T cell acute lymphocytic leukemia protein 1; thrombopoietin receptor; transcription factor GATA 1; transcription factor GATA 2; unclassified drug; von Willebrand factor; amino acid sequence; Article; binding affinity; binding site; cell differentiation; cell division; cell proliferation; complementarity determining region; controlled study; dimerization; disease association; down regulation; fluorescence activated cell sorting; gene expression; hematopoietic stem cell; human; human cell; in vitro study; megakaryocyte; nonhuman; pathogenesis; priority journal; protein binding; protein expression; protein localization; protein phosphorylation; RNA sequencing; signal transduction; stem cell self-renewal; thrombotic thrombocytopenic purpura; upregulation
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/181051
作者单位	Department of Pathology, Stanford University, School of Medicine, Stanford, CA 94305, United States; HHMI, Stanford University, School of Medicine, Stanford, CA 94305, United States; Department of Molecular and Cellular Physiology, Stanford University, School of Medicine, Stanford, CA 94305, United States; Department of Structural Biology, Stanford University, School of Medicine, Stanford, CA 94305, United States; School of Life Sciences, University of Dundee, Dundee, DD15EH, United Kingdom; York Biomedical Research Institute, Department of Biology, University of York, Heslington, YO10 5DD, United Kingdom; Department of Medicine, Division of Hematology, Stanford University, School of Medicine, Stanford, CA 94305, United States; Department of Bioengineering, School of Bioengineering and Medicine, Stanford University, Stanford, CA 94305, United States; Microchemistry, Proteomics, Lipidomics and NGS Department, Genentech Inc., South San Francisco, CA 94080, United States; Department of Oncology-Pathol...
推荐引用方式 GB/T 7714	Cui L.,Moraga I.,Lerbs T.,et al. Tuning MPL signaling to influence hematopoietic stem cell differentiation and inhibit essential thrombocythemia progenitors[J],2021,118(2).
APA	Cui L..,Moraga I..,Lerbs T..,van Neste C..,Wilmes S..,...&Wernig G..(2021).Tuning MPL signaling to influence hematopoietic stem cell differentiation and inhibit essential thrombocythemia progenitors.Proceedings of the National Academy of Sciences of the United States of America,118(2).
MLA	Cui L.,et al."Tuning MPL signaling to influence hematopoietic stem cell differentiation and inhibit essential thrombocythemia progenitors".Proceedings of the National Academy of Sciences of the United States of America 118.2(2021).