DC Element | Wert | Sprache |
dc.contributor.author | Cui, Lu | |
dc.contributor.author | Moraga, Ignacio | |
dc.contributor.author | Lerbs, Tristan | |
dc.contributor.author | Van Neste, Camille | |
dc.contributor.author | Wilmes, Stephan | |
dc.contributor.author | Tsutsumi, Naotaka | |
dc.contributor.author | Trotman-Grant, Aaron Claudius | |
dc.contributor.author | Gakovic, Milica | |
dc.contributor.author | Andrews, Sarah | |
dc.contributor.author | Gotlib, Jason | |
dc.contributor.author | Darmanis, Spyros | |
dc.contributor.author | Enge, Martin | |
dc.contributor.author | Quake, Stephen | |
dc.contributor.author | Hitchcock, Ian S. | |
dc.contributor.author | Piehler, Jacob | |
dc.contributor.author | Garcia, K. Christopher | |
dc.contributor.author | Wernig, Gerlinde | |
dc.date.accessioned | 2021-12-23T16:23:12Z | - |
dc.date.available | 2021-12-23T16:23:12Z | - |
dc.date.issued | 2021 | |
dc.identifier.issn | 00278424 | |
dc.identifier.uri | https://osnascholar.ub.uni-osnabrueck.de/handle/unios/14453 | - |
dc.description.abstract | 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. | |
dc.description.sponsorship | Ludwig Institute; Mathers Foundation; HHMIHoward Hughes Medical Institute; Cancer Research UKCancer Research UK [A24593]; University of York Technology Facility; [NIH-RO1-AI51321]; K.C.G. acknowledges NIH-RO1-AI51321, the Ludwig Institute, the Mathers Foundation, and HHMI for funding; G.W. acknowledges the National Heart, Lung, and Blood Institute, the Ludwig Institute, Scleroderma Research Foundation (SRF), and the Emmerson Collective. Deutsche Forschungsgesellschaft (DFG) provided salary support to T.L. and I.S.H. was supported by Cancer Research UK grant A24593 and by the University of York Technology Facility. | |
dc.language.iso | en | |
dc.publisher | NATL ACAD SCIENCES | |
dc.relation.ispartof | PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | |
dc.subject | C-MPL | |
dc.subject | EXPANSION | |
dc.subject | hematopoietic stem cells | |
dc.subject | MEGAKARYOCYTOPOIESIS | |
dc.subject | megakaryopoiesis | |
dc.subject | MEMBER | |
dc.subject | MOLECULAR-CLONING | |
dc.subject | Multidisciplinary Sciences | |
dc.subject | MUTATIONS | |
dc.subject | myeloproliferative neoplasm | |
dc.subject | RECEPTOR | |
dc.subject | Science & Technology - Other Topics | |
dc.subject | STIMULATION | |
dc.subject | THROMBOCYTOPENIA | |
dc.subject | THROMBOPOIETIN | |
dc.subject | thrombopoietin signaling | |
dc.title | Tuning MPL signaling to influence hematopoietic stem cell differentiation and inhibit essential thrombocythemia progenitors | |
dc.type | journal article | |
dc.identifier.doi | 10.1073/pnas.2017849118 | |
dc.identifier.isi | ISI:000607277100073 | |
dc.description.volume | 118 | |
dc.description.issue | 2 | |
dc.contributor.orcid | 0000-0001-9909-0701 | |
dc.contributor.orcid | 0000-0002-8358-9986 | |
dc.contributor.orcid | 0000-0002-4112-710X | |
dc.contributor.orcid | 0000-0002-9177-8699 | |
dc.contributor.orcid | 0000-0001-8748-8931 | |
dc.contributor.orcid | 0000-0002-3531-8102 | |
dc.contributor.orcid | 0000-0002-3617-7145 | |
dc.publisher.place | 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA | |
dcterms.isPartOf.abbreviation | Proc. Natl. Acad. Sci. U. S. A. | |
dcterms.oaStatus | Green Published, hybrid | |
crisitem.author.dept | FB 05 - Biologie/Chemie | - |
crisitem.author.deptid | fb05 | - |
crisitem.author.orcid | 0000-0002-2143-2270 | - |
crisitem.author.parentorg | Universität Osnabrück | - |
crisitem.author.netid | PiJa938 | - |