{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMPL, the thrombopoietin receptor, is a central regulator of hematopoiesis that promotes hematopoietic stem cell renewal, megakaryocyte differentiation, and platelet formation through the activation of JAK‐STAT, PI3‐kinase, and MAP kinase pathways. In its normal function, MPL requires binding to its ligand thrombopoietin and is tightly controlled by mechanisms that ensure proper receptor trafficking, surface expression, and degradation (for example, via specific YXXΦ motifs and glycosylation). This precise control is essential for balanced signaling and cellular homeostasis in the hematopoietic compartment."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA spectrum of activating (gain‐of‐function) mutations in MPL has been identified, many clustering in exon 10 (notably at residues W515 and S505) that lead to ligand‐independent receptor dimerization and constitutive downstream JAK2 signaling. Such mutations are found in patients with myeloproliferative neoplasms—including essential thrombocythemia and myelofibrosis—and can be further potentiated by aberrant interactions with mutant calreticulin, which specifically engages MPL to drive oncogenic transformation. Moreover, additional variants (for example, novel mutations like p.Pro106Leu or polymorphisms such as K39N) alter receptor processing or signaling amplitude and thereby contribute to distinct clinical phenotypes. These studies, employing both functional assays and advanced mutation detection techniques, underscore how structural perturbations of the transmembrane and cytoplasmic domains of MPL (including alterations in dimeric orientation) translate into abnormal hematopoietic proliferation and differentiation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "32"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nConversely, loss‐of‐function MPL mutations and certain germline polymorphisms have been implicated in congenital amegakaryocytic thrombocytopenia and familial thrombocytosis, where deficient receptor expression or misprocessing leads to impaired megakaryocyte development. In some settings, MPL expression is also modulated by upstream transcriptional regulators (for instance, as influenced by AML1 binding in familial platelet disorders) or by microRNAs in nonhematopoietic contexts, thereby highlighting the receptor’s broader biological impact. In addition, careful analyses of MPL mutation allele burdens, copy‐neutral loss of heterozygosity, and haplotype backgrounds have refined our understanding of MPL’s role in defining disease phenotype, prognosis, and response to targeted therapeutics."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "33", "end_ref": "44"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yana Pikman, Benjamin H Lee, Thomas Mercher, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Med (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pmed.0030270"}], "href": "https://doi.org/10.1371/journal.pmed.0030270"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16834459"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16834459"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Jacob Grinfeld, Jyoti Nangalia, E Joanna Baxter, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Classification and Personalized Prognosis in Myeloproliferative Neoplasms."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "N Engl J Med (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1056/NEJMoa1716614"}], "href": "https://doi.org/10.1056/NEJMoa1716614"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30304655"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30304655"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "A Tefferi, T L Lasho, O Abdel-Wahab, et al. "}, {"type": "b", "children": [{"type": "t", "text": "IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Leukemia (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/leu.2010.113"}], "href": "https://doi.org/10.1038/leu.2010.113"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20508616"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20508616"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Yohan Royer, Judith Staerk, Marcel Costuleanu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Janus kinases affect thrombopoietin receptor cell surface localization and stability."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M501376200"}], "href": "https://doi.org/10.1074/jbc.M501376200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15899890"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15899890"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "O Kilpivaara, R L Levine "}, {"type": "b", "children": [{"type": "t", "text": "JAK2 and MPL mutations in myeloproliferative neoplasms: discovery and science."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Leukemia (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/leu.2008.229"}], "href": "https://doi.org/10.1038/leu.2008.229"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18754026"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18754026"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Ayalew Tefferi "}, {"type": "b", "children": [{"type": "t", "text": "JAK and MPL mutations in myeloid malignancies."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Leuk Lymphoma (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/10428190801895360"}], "href": "https://doi.org/10.1080/10428190801895360"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18297515"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18297515"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Erin E Matthews, Damien Thévenin, Julia M Rogers, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thrombopoietin receptor activation: transmembrane helix dimerization, rotation, and allosteric modulation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FASEB J (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1096/fj.10-178673"}], "href": "https://doi.org/10.1096/fj.10-178673"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21402716"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21402716"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "A Pardanani, P Guglielmelli, T L Lasho, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Primary myelofibrosis with or without mutant MPL: comparison of survival and clinical features involving 603 patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Leukemia (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/leu.2011.161"}], "href": "https://doi.org/10.1038/leu.2011.161"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21691276"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21691276"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Judith Staerk, Jean-Philippe Defour, Christian Pecquet, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Orientation-specific signalling by thrombopoietin receptor dimers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/emboj.2011.315"}], "href": "https://doi.org/10.1038/emboj.2011.315"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21892137"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21892137"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Animesh D Pardanani, Ross L Levine, Terra Lasho, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2006-04-018879"}], "href": "https://doi.org/10.1182/blood-2006-04-018879"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16868251"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16868251"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "A Tefferi, T L Lasho, C M Finke, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Leukemia (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/leu.2014.3"}], "href": "https://doi.org/10.1038/leu.2014.3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24402162"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24402162"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Philip A Beer, Peter J Campbell, Linda M Scott, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2008-01-131664"}], "href": "https://doi.org/10.1182/blood-2008-01-131664"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18451306"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18451306"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Elisa Rumi, Daniela Pietra, Cristiana Pascutto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2014-05-578435"}], "href": "https://doi.org/10.1182/blood-2014-05-578435"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24986690"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24986690"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Ilyas Chachoua, Christian Pecquet, Mira El-Khoury, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thrombopoietin receptor activation by myeloproliferative neoplasm associated calreticulin mutants."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2015-11-681932"}], "href": "https://doi.org/10.1182/blood-2015-11-681932"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26668133"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26668133"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Jianmin Ding, Hirokazu Komatsu, Atsushi Wakita, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Familial essential thrombocythemia associated with a dominant-positive activating mutation of the c-MPL gene, which encodes for the receptor for thrombopoietin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2003-10-3471"}], "href": "https://doi.org/10.1182/blood-2003-10-3471"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14764528"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14764528"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Shannon Elf, Nouran S Abdelfattah, Edwin Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutant Calreticulin Requires Both Its Mutant C-terminus and the Thrombopoietin Receptor for Oncogenic Transformation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Discov (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/2159-8290.CD-15-1434"}], "href": "https://doi.org/10.1158/2159-8290.CD-15-1434"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26951227"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26951227"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Marito Araki, Yinjie Yang, Nami Masubuchi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Activation of the thrombopoietin receptor by mutant calreticulin in CALR-mutant myeloproliferative neoplasms."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2015-09-671172"}], "href": "https://doi.org/10.1182/blood-2015-09-671172"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26817954"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26817954"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Alessandro M Vannucchi, Elisabetta Antonioli, Paola Guglielmelli, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characteristics and clinical correlates of MPL 515W>L/K mutation in essential thrombocythemia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2008-01-135897"}], "href": "https://doi.org/10.1182/blood-2008-01-135897"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18519816"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18519816"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Xénia Cabagnols, Fabrizia Favale, Florence Pasquier, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Presence of atypical thrombopoietin receptor (MPL) mutations in triple-negative essential thrombocythemia patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2015-07-661983"}], "href": "https://doi.org/10.1182/blood-2015-07-661983"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26450985"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26450985"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Paola Guglielmelli, Alessandro Pancrazzi, Gaetano Bergamaschi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Anaemia characterises patients with myelofibrosis harbouring Mpl mutation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Haematol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1365-2141.2007.06565.x"}], "href": "https://doi.org/10.1111/j.1365-2141.2007.06565.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17408465"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17408465"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "R Chaligné, C Tonetti, R Besancenot, et al. "}, {"type": "b", "children": [{"type": "t", "text": "New mutations of MPL in primitive myelofibrosis: only the MPL W515 mutations promote a G1/S-phase transition."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Leukemia (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/leu.2008.137"}], "href": "https://doi.org/10.1038/leu.2008.137"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18528423"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18528423"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Elaine M Boyd, Anthony J Bench, Andrea Goday-Fernández, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Clinical utility of routine MPL exon 10 analysis in the diagnosis of essential thrombocythaemia and primary myelofibrosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Haematol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1365-2141.2010.08083.x"}], "href": "https://doi.org/10.1111/j.1365-2141.2010.08083.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20151976"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20151976"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Elisa Rumi, Daniela Pietra, Paola Guglielmelli, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Acquired copy-neutral loss of heterozygosity of chromosome 1p as a molecular event associated with marrow fibrosis in MPL-mutated myeloproliferative neoplasms."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2013-02-486050"}], "href": "https://doi.org/10.1182/blood-2013-02-486050"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23575445"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23575445"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Donna M Williams, Ann H Kim, Ophelia Rogers, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Phenotypic variations and new mutations in JAK2 V617F-negative polycythemia vera, erythrocytosis, and idiopathic myelofibrosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Hematol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.exphem.2007.08.010"}], "href": "https://doi.org/10.1016/j.exphem.2007.08.010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17920755"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17920755"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Christian Pecquet, Judith Staerk, Ronan Chaligné, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Induction of myeloproliferative disorder and myelofibrosis by thrombopoietin receptor W515 mutants is mediated by cytosolic tyrosine 112 of the receptor."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2008-10-183558"}], "href": "https://doi.org/10.1182/blood-2008-10-183558"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19996410"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19996410"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Luciana Teofili, Fiorina Giona, Lorenza Torti, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Hereditary thrombocytosis caused by MPLSer505Asn is associated with a high thrombotic risk, splenomegaly and progression to bone marrow fibrosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Haematologica (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3324/haematol.2009.007542"}], "href": "https://doi.org/10.3324/haematol.2009.007542"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19713221"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19713221"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "El-Harith Abdelghaffar El-Harith, Cornelia Roesl, Matthias Ballmaier, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Familial thrombocytosis caused by the novel germ-line mutation p.Pro106Leu in the MPL gene."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Haematol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1365-2141.2008.07430.x"}], "href": "https://doi.org/10.1111/j.1365-2141.2008.07430.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19036112"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19036112"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Daniela Pietra, Angela Brisci, Elisa Rumi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Deep sequencing reveals double mutations in cis of MPL exon 10 in myeloproliferative neoplasms."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Haematologica (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3324/haematol.2010.034793"}], "href": "https://doi.org/10.3324/haematol.2010.034793"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21228032"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21228032"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Jean-Philippe Defour, Miki Itaya, Vitalina Gryshkova, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tryptophan at the transmembrane-cytosolic junction modulates thrombopoietin receptor dimerization and activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1211560110"}], "href": "https://doi.org/10.1073/pnas.1211560110"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23359689"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23359689"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Jianmin Ding, Hirokazu Komatsu, Shinsuke Iida, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Asn505 mutation of the c-MPL gene, which causes familial essential thrombocythemia, induces autonomous homodimerization of the c-Mpl protein due to strong amino acid polarity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2008-04-149047"}], "href": "https://doi.org/10.1182/blood-2008-04-149047"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19483125"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19483125"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "Lijuan Han, Claudia Schubert, Johanna Köhler, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Calreticulin-mutant proteins induce megakaryocytic signaling to transform hematopoietic cells and undergo accelerated degradation and Golgi-mediated secretion."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Hematol Oncol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13045-016-0275-0"}], "href": "https://doi.org/10.1186/s13045-016-0275-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27177927"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27177927"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Animesh Pardanani, Terra L Lasho, Christy Finke, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Extending Jak2V617F and MplW515 mutation analysis to single hematopoietic colonies and B and T lymphocytes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Stem Cells (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1634/stemcells.2007-0175"}], "href": "https://doi.org/10.1634/stemcells.2007-0175"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17540852"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17540852"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "Jean-Jacques Kiladjian, Francisco Cervantes, Franck W G Leebeek, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The impact of JAK2 and MPL mutations on diagnosis and prognosis of splanchnic vein thrombosis: a report on 241 cases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2007-11-125328"}], "href": "https://doi.org/10.1182/blood-2007-11-125328"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18250227"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18250227"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "A Pardanani, T L Lasho, C M Finke, et al. "}, {"type": "b", "children": [{"type": "t", "text": "IDH1 and IDH2 mutation analysis in chronic- and blast-phase myeloproliferative neoplasms."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Leukemia (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/leu.2010.77"}], "href": "https://doi.org/10.1038/leu.2010.77"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20410924"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20410924"}]}, {"type": "r", "ref": 35, "children": [{"type": "t", "text": "Wenchao Gao, Lu Chen, Zhenyu Ma, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Isolation and phenotypic characterization of colorectal cancer stem cells with organ-specific metastatic potential."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gastroenterology (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1053/j.gastro.2013.05.049"}], "href": "https://doi.org/10.1053/j.gastro.2013.05.049"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23747337"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23747337"}]}, {"type": "r", "ref": 36, "children": [{"type": "t", "text": "Alison R Moliterno, Donna M Williams, Laura I Gutierrez-Alamillo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mpl Baltimore: a thrombopoietin receptor polymorphism associated with thrombocytosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0404241101"}], "href": "https://doi.org/10.1073/pnas.0404241101"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15269348"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15269348"}]}, {"type": "r", "ref": 37, "children": [{"type": "t", "text": "Matthias Ballmaier, Manuela Germeshausen "}, {"type": "b", "children": [{"type": "t", "text": "Congenital amegakaryocytic thrombocytopenia: clinical presentation, diagnosis, and treatment."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Semin Thromb Hemost (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1055/s-0031-1291377"}], "href": "https://doi.org/10.1055/s-0031-1291377"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22102270"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22102270"}]}, {"type": "r", "ref": 38, "children": [{"type": "t", "text": "Manuela Germeshausen, Matthias Ballmaier, Karl Welte "}, {"type": "b", "children": [{"type": "t", "text": "MPL mutations in 23 patients suffering from congenital amegakaryocytic thrombocytopenia: the type of mutation predicts the course of the disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mutat (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/humu.9415"}], "href": "https://doi.org/10.1002/humu.9415"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16470591"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16470591"}]}, {"type": "r", "ref": 39, "children": [{"type": "t", "text": "M M Patnaik, T L Lasho, C M Finke, et al. "}, {"type": "b", "children": [{"type": "t", "text": "WHO-defined 'myelodysplastic syndrome with isolated del(5q)' in 88 consecutive patients: survival data, leukemic transformation rates and prevalence of JAK2, MPL and IDH mutations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Leukemia (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/leu.2010.105"}], "href": "https://doi.org/10.1038/leu.2010.105"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20485371"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20485371"}]}, {"type": "r", "ref": 40, "children": [{"type": "t", "text": "Ronan Chaligné, Chloé James, Carole Tonetti, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Evidence for MPL W515L/K mutations in hematopoietic stem cells in primitive myelofibrosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2007-05-089003"}], "href": "https://doi.org/10.1182/blood-2007-05-089003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17709604"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17709604"}]}, {"type": "r", "ref": 41, "children": [{"type": "t", "text": "Amy V Jones, Peter J Campbell, Philip A Beer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The JAK2 46/1 haplotype predisposes to MPL-mutated myeloproliferative neoplasms."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2009-08-236448"}], "href": "https://doi.org/10.1182/blood-2009-08-236448"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20304805"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20304805"}]}, {"type": "r", "ref": 42, "children": [{"type": "t", "text": "Ian S Hitchcock, Maximus M Chen, Jennifer R King, et al. "}, {"type": "b", "children": [{"type": "t", "text": "YRRL motifs in the cytoplasmic domain of the thrombopoietin receptor regulate receptor internalization and degradation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2008-01-134049"}], "href": "https://doi.org/10.1182/blood-2008-01-134049"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18487512"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18487512"}]}, {"type": "r", "ref": 43, "children": [{"type": "t", "text": "Seyedtaghi Takyar, Hema Vasavada, Jian-ge Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "VEGF controls lung Th2 inflammation via the miR-1-Mpl (myeloproliferative leukemia virus oncogene)-P-selectin axis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20121200"}], "href": "https://doi.org/10.1084/jem.20121200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24043765"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24043765"}]}, {"type": "r", "ref": 44, "children": [{"type": "t", "text": "Paula G Heller, Ana C Glembotsky, Manish J Gandhi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Low Mpl receptor expression in a pedigree with familial platelet disorder with predisposition to acute myelogenous leukemia and a novel AML1 mutation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2005-01-0050"}], "href": "https://doi.org/10.1182/blood-2005-01-0050"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15741216"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15741216"}]}]}]}