{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T09:50:32Z","timestamp":1787824232477,"version":"build-2784847793"},"reference-count":49,"publisher":"National Academy of Sciences","issue":"2","license":[{"start":{"date-parts":[[2020,12,31]],"date-time":"2020-12-31T00:00:00Z","timestamp":1609372800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["NIH-RO1-AI51321"],"award-info":[{"award-number":["NIH-RO1-AI51321"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"HHS","award":["1222520-700-WAKCB"],"award-info":[{"award-number":["1222520-700-WAKCB"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2021,1,12]]},"abstract":"<jats:title>Significance<\/jats:title>\n                  <jats:p>TPO is a cytokine that signals through the receptor MPL (or TPO-R), and is essential for megakaryocyte differentiation and maintenance of hematopoietic stem cells (HSCs). TPO signaling is deregulated in essential thrombocythemia (ET). Here, we engineered diabodies (DBs) against the TPO-R ECD as surrogate TPO ligands to manipulate TPO-R signaling, from full to partial agonism, and that show decoupling of the dual functions of TPO\/TPO-R (i.e, HSC maintenance versus megakaryopoiesis). We subsequently discovered that partial agonistic DBs, by reducing the strength of the TPO-R signal, not only preserved HSCs in culture, but also blocked oncogenic signaling in ET. This finding has the potential to improve HSC cultures for transplants, as well as serve as a unique therapeutic approach for ET.<\/jats:p>","DOI":"10.1073\/pnas.2017849118","type":"journal-article","created":{"date-parts":[[2020,12,31]],"date-time":"2020-12-31T14:01:25Z","timestamp":1609423285000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":30,"title":["Tuning MPL signaling to influence hematopoietic stem cell differentiation and inhibit essential thrombocythemia progenitors"],"prefix":"10.1073","volume":"118","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3531-8102","authenticated-orcid":false,"given":"Lu","family":"Cui","sequence":"first","affiliation":[{"name":"Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignacio","family":"Moraga","sequence":"additional","affiliation":[{"name":"HHMI, Stanford University School of Medicine, Stanford, CA 94305;"},{"name":"Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305;"},{"name":"Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305;"},{"name":"School of Life Sciences, University of Dundee, Dundee DD15EH, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tristan","family":"Lerbs","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camille","family":"Van Neste","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4112-710X","authenticated-orcid":false,"given":"Stephan","family":"Wilmes","sequence":"additional","affiliation":[{"name":"School of Life Sciences, University of Dundee, Dundee DD15EH, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3617-7145","authenticated-orcid":false,"given":"Naotaka","family":"Tsutsumi","sequence":"additional","affiliation":[{"name":"HHMI, Stanford University School of Medicine, Stanford, CA 94305;"},{"name":"Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305;"},{"name":"Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron Claudius","family":"Trotman-Grant","sequence":"additional","affiliation":[{"name":"HHMI, Stanford University School of Medicine, Stanford, CA 94305;"},{"name":"Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305;"},{"name":"Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9177-8699","authenticated-orcid":false,"given":"Milica","family":"Gakovic","sequence":"additional","affiliation":[{"name":"HHMI, Stanford University School of Medicine, Stanford, CA 94305;"},{"name":"Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305;"},{"name":"Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305;"},{"name":"School of Life Sciences, University of Dundee, Dundee DD15EH, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Andrews","sequence":"additional","affiliation":[{"name":"York Biomedical Research Institute, Department of Biology, University of York, Heslington, YO10 5DD York, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Gotlib","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Spyros","family":"Darmanis","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, School of Bioengineering and Medicine, Stanford University, Stanford, CA 94305;"},{"name":"Microchemistry, Proteomics, Lipidomics and NGS Department Genentech Inc., South San Francisco, CA, 94080;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Enge","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, School of Bioengineering and Medicine, Stanford University, Stanford, CA 94305;"},{"name":"Department of Oncology-Pathology Karolinska Institutet, 171 64 Stockholm, Sweden;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Quake","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, School of Bioengineering and Medicine, Stanford University, Stanford, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian S.","family":"Hitchcock","sequence":"additional","affiliation":[{"name":"York Biomedical Research Institute, Department of Biology, University of York, Heslington, YO10 5DD York, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2143-2270","authenticated-orcid":false,"given":"Jacob","family":"Piehler","sequence":"additional","affiliation":[{"name":"Department of Biology and Center for Cellular Nanoanalytics (CellNanOs), University of Osnabr\u00fcck, Barbarastra\u00dfe 11, 49076 Osnabr\u00fcck, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. Christopher","family":"Garcia","sequence":"additional","affiliation":[{"name":"HHMI, Stanford University School of Medicine, Stanford, CA 94305;"},{"name":"Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305;"},{"name":"Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5169-8731","authenticated-orcid":false,"given":"Gerlinde","family":"Wernig","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305;"},{"name":"Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2020,12,31]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/369565a0"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/369571a0"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/369533a0"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/369568a0"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.12.5640"},{"key":"e_1_3_4_6_2","first-page":"2607","article-title":"Characterization of the murine Mpl proto-oncogene, a member of the hematopoietic cytokine receptor family: Molecular cloning, chromosomal location and evidence for a function in cell growth","volume":"8","author":"Vigon I.","year":"1993","unstructured":"I. Vigon ., Characterization of the murine Mpl proto-oncogene, a member of the hematopoietic cytokine receptor family: Molecular cloning, chromosomal location and evidence for a function in cell growth. 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