{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T14:15:07Z","timestamp":1790000107722,"version":"4.0.1"},"reference-count":28,"publisher":"American Society of Hematology","issue":"4","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,1,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The single transmembrane domain (TMD) of the human thrombopoietin receptor (TpoR\/myeloproliferative leukemia [MPL] protein), encoded by exon 10 of the MPL gene, is a hotspot for somatic mutations associated with myeloproliferative neoplasms (MPNs). Approximately 6% and 14% of JAK2 V617F\u2212 essential thrombocythemia and primary myelofibrosis patients, respectively, have \u201ccanonical\u201d MPL exon 10 driver mutations W515L\/K\/R\/A or S505N, which generate constitutively active receptors and consequent loss of Tpo dependence. Other \u201cnoncanonical\u201d MPL exon 10 mutations have also been identified in patients, both alone and in combination with canonical mutations, but, in almost all cases, their functional consequences and relevance to disease are unknown. Here, we used a deep mutational scanning approach to evaluate all possible single amino acid substitutions in the human TpoR TMD for their ability to confer cytokine-independent growth in Ba\/F3 cells. We identified all currently recognized driver mutations and 7 novel mutations that cause constitutive TpoR activation, and a much larger number of second-site mutations that enhance S505N-driven activation. We found examples of both of these categories in published and previously unpublished MPL exon 10 sequencing data from MPN patients, demonstrating that some, if not all, of the new mutations reported here represent likely drivers or modifiers of myeloproliferative disease.<\/jats:p>","DOI":"10.1182\/blood.2019002561","type":"journal-article","created":{"date-parts":[[2019,10,14]],"date-time":"2019-10-14T16:02:10Z","timestamp":1571068930000},"page":"287-292","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":50,"title":["Novel drivers and modifiers of MPL-dependent oncogenic transformation identified by deep mutational scanning"],"prefix":"10.1182","volume":"135","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8381-1121","authenticated-orcid":false,"given":"Jessica L.","family":"Bridgford","sequence":"first","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia;"},{"name":"Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su Min","family":"Lee","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia;"},{"name":"Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine M. M.","family":"Lee","sequence":"additional","affiliation":[{"name":"The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1809-284X","authenticated-orcid":false,"given":"Paola","family":"Guglielmelli","sequence":"additional","affiliation":[{"name":"Centro di Ricerca e Innovazione per le Malattie Mieloproliferative (CRIMM), Azienda Ospedaliera Universitaria Careggi, Dipartimento di Medicina Sperimentale e Clinica, Universit\u00e0 degli Studi, Florence, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7572-9504","authenticated-orcid":false,"given":"Elisa","family":"Rumi","sequence":"additional","affiliation":[{"name":"Department of Hematology Oncology, Unit\u00e0 Operativa Complessa (UOC) Ematologia, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy;"},{"name":"Department of Molecular Medicine, University of Pavia, Pavia, Italy; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6575-8766","authenticated-orcid":false,"given":"Daniela","family":"Pietra","sequence":"additional","affiliation":[{"name":"Department of Hematology Oncology, Unit\u00e0 Operativa Complessa (UOC) Ematologia, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy;"},{"name":"Department of Molecular Medicine, University of Pavia, Pavia, Italy; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Wilcox","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia;"},{"name":"Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2883-4675","authenticated-orcid":false,"given":"Yash","family":"Chhabra","sequence":"additional","affiliation":[{"name":"The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1474-605X","authenticated-orcid":false,"given":"Alan F.","family":"Rubin","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia;"},{"name":"Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia;"},{"name":"Bioinformatics and Cancer Genomics Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6984-8817","authenticated-orcid":false,"given":"Mario","family":"Cazzola","sequence":"additional","affiliation":[{"name":"Department of Hematology Oncology, Unit\u00e0 Operativa Complessa (UOC) Ematologia, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy;"},{"name":"Department of Molecular Medicine, University of Pavia, Pavia, Italy; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5755-0730","authenticated-orcid":false,"given":"Alessandro M.","family":"Vannucchi","sequence":"additional","affiliation":[{"name":"Centro di Ricerca e Innovazione per le Malattie Mieloproliferative (CRIMM), Azienda Ospedaliera Universitaria Careggi, Dipartimento di Medicina Sperimentale e Clinica, Universit\u00e0 degli Studi, Florence, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2691-1668","authenticated-orcid":false,"given":"Andrew J.","family":"Brooks","sequence":"additional","affiliation":[{"name":"The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5846-6469","authenticated-orcid":false,"given":"Matthew E.","family":"Call","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia;"},{"name":"Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7684-5841","authenticated-orcid":false,"given":"Melissa J.","family":"Call","sequence":"additional","affiliation":[{"name":"The Walter and Eliza Hall Institute of 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