{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T00:21:00Z","timestamp":1758846060633,"version":"3.44.0"},"reference-count":72,"publisher":"BMJ","issue":"11","content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Clin Pathol"],"accepted":{"date-parts":[[2016,3,10]]},"published-print":{"date-parts":[[2016,11]]},"abstract":"<jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>Megakaryocyte expansion in myeloproliferative neoplasms (MPNs) is due to uncontrolled proliferation accompanied by dysregulation of proapoptotic and antiapoptotic mechanisms. Here we have investigated the intrinsic and extrinsic apoptotic pathways of megakaryocytes in human MPNs to further define the mechanisms involved.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>The megakaryocytic expression of proapoptotic caspase-8, caspase-9, Diablo, p53 and antiapoptotic survivin proteins was investigated in bone marrow specimens of the MPNs (n=145) and controls (n=15) using immunohistochemistry. The megakaryocyte percentage positivity was assessed by light microscopy and correlated with the MPN entity, <jats:italic>JAK2<\/jats:italic>\n                     <jats:sup>V617F<\/jats:sup>\/<jats:italic>CALR<\/jats:italic> mutation status and platelet count.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The proportion of megakaryocytes in the MPNs expressing caspase-8, caspase-9, Diablo, survivin and p53 was significantly greater than controls. A greater proportion of myeloproliferative megakaryocytes expressed survivin relative to its reciprocal inhibitor, Diablo. Differences were seen between myelofibrosis, polycythaemia vera and essential thrombocythaemia for caspase-9 and p53. <jats:italic>CALR<\/jats:italic>-mutated cases had greater megakaryocyte p53 positivity compared to those with the <jats:italic>JAK2<\/jats:italic>\n                     <jats:sup>V617F<\/jats:sup> mutation. Proapoptotic caspase-9 expression showed a positive correlation with platelet count, which was most marked in myelofibrosis and <jats:italic>CALR<\/jats:italic>-mutated cases.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Disruptions targeting the intrinsic apoptotic cascade promote megakaryocyte hyperplasia and thrombocytosis in the MPNs. There is progressive dysfunction of apoptosis as evidenced by the marked reduction in proapoptotic caspase-9 and accumulation of p53 in myelofibrosis. The dysfunction of caspase-9, which is necessary for proplatelet formation, may be the mechanism for the excess thrombocytosis associated with <jats:italic>CALR<\/jats:italic> mutations. Survivin seems to be the key protein mediating the megakaryocyte survival signature in the MPNs and is a potential therapeutic target.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jclinpath-2016-203625","type":"journal-article","created":{"date-parts":[[2016,4,8]],"date-time":"2016-04-08T23:29:41Z","timestamp":1460158181000},"page":"1017-1024","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":11,"title":["Dysregulation of the intrinsic apoptotic pathway mediates megakaryocytic hyperplasia in myeloproliferative neoplasms"],"prefix":"10.1136","volume":"69","author":[{"given":"Jacques A J","family":"Malherbe","sequence":"first","affiliation":[{"name":"School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathryn A","family":"Fuller","sequence":"additional","affiliation":[{"name":"School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia"},{"name":"PathWest Laboratory Medicine, Nedlands, Western Australia, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bob","family":"Mirzai","sequence":"additional","affiliation":[{"name":"School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia"},{"name":"PathWest Laboratory Medicine, Nedlands, Western Australia, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon","family":"Kavanagh","sequence":"additional","affiliation":[{"name":"School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia"},{"name":"PathWest Laboratory Medicine, Nedlands, Western Australia, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chi-Chiu","family":"So","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Medicine, University of Hong Kong, Hong Kong, Hong Kong"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ho-Wan","family":"Ip","sequence":"additional","affiliation":[{"name":"Department of Pathology & Clinical Biochemistry, Queen Mary Hospital, Hong Kong, Hong Kong"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Belinda B","family":"Guo","sequence":"additional","affiliation":[{"name":"School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cecily","family":"Forsyth","sequence":"additional","affiliation":[{"name":"Jarrett Street Specialist Centre, North Gosford, New South Wales, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca","family":"Howman","sequence":"additional","affiliation":[{"name":"PathWest Laboratory Medicine, Nedlands, Western Australia, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wendy N","family":"Erber","sequence":"additional","affiliation":[{"name":"School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia"},{"name":"PathWest Laboratory Medicine, Nedlands, Western Australia, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2016,4,8]]},"reference":[{"key":"2025092509182442000_69.11.1017.1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03546"},{"key":"2025092509182442000_69.11.1017.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2005.03.023"},{"key":"2025092509182442000_69.11.1017.3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)71142-9"},{"key":"2025092509182442000_69.11.1017.4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1311347"},{"key":"2025092509182442000_69.11.1017.5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1312542"},{"key":"2025092509182442000_69.11.1017.6","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-04-083501"},{"key":"2025092509182442000_69.11.1017.7","unstructured":"Swerdlow SH , Campo E , Harris NL , et al . WHO classification of tumours, Volume 2. 4th edn. Geneva: WHO, 2008; WHO classification of tumours of haematopoietic and lymphoid tissues."},{"key":"2025092509182442000_69.11.1017.8","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.29.8711"},{"key":"2025092509182442000_69.11.1017.9","doi-asserted-by":"publisher","DOI":"10.1136\/jcp.2007.054353"},{"key":"2025092509182442000_69.11.1017.10","doi-asserted-by":"publisher","DOI":"10.1136\/jcp.2010.080895"},{"key":"2025092509182442000_69.11.1017.11","doi-asserted-by":"publisher","DOI":"10.1007\/s12032-012-0202-3"},{"key":"2025092509182442000_69.11.1017.12","doi-asserted-by":"publisher","DOI":"10.1159\/000356187"},{"key":"2025092509182442000_69.11.1017.13","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1136\/jclinpath-2015-203177","article-title":"Megakaryocytic hyperplasia is driven by disordered proliferative, apoptotic and epigenetic mechanisms","volume":"62","author":"Malherbe","year":"2016","journal-title":"J Clin Path"},{"key":"2025092509182442000_69.11.1017.14","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2009.066944"},{"key":"2025092509182442000_69.11.1017.15","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2011.30"},{"key":"2025092509182442000_69.11.1017.16","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2184.2012.00845.x"},{"key":"2025092509182442000_69.11.1017.17","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-07-367532"},{"key":"2025092509182442000_69.11.1017.18","first-page":"924","article-title":"Dysfunctional apoptosome activation in ovarian cancer: implications for chemoresistance","volume":"62","author":"Liu","year":"2002","journal-title":"Cancer Res"},{"key":"2025092509182442000_69.11.1017.19","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddl119"},{"key":"2025092509182442000_69.11.1017.20","doi-asserted-by":"publisher","DOI":"10.1245\/s10434-009-0488-3"},{"key":"2025092509182442000_69.11.1017.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2012.02.009"},{"key":"2025092509182442000_69.11.1017.22","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2013.378"},{"key":"2025092509182442000_69.11.1017.23","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2015.192"},{"key":"2025092509182442000_69.11.1017.24","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-03-0686"},{"key":"2025092509182442000_69.11.1017.25","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-11-394858"},{"key":"2025092509182442000_69.11.1017.26","doi-asserted-by":"publisher","DOI":"10.1038\/35022514"},{"key":"2025092509182442000_69.11.1017.27","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200422222"},{"key":"2025092509182442000_69.11.1017.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2006.03.007"},{"key":"2025092509182442000_69.11.1017.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2006.12.020"},{"key":"2025092509182442000_69.11.1017.30","doi-asserted-by":"publisher","DOI":"10.1016\/j.humpath.2006.06.006"},{"key":"2025092509182442000_69.11.1017.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.leukres.2009.11.030"},{"key":"2025092509182442000_69.11.1017.32","doi-asserted-by":"publisher","DOI":"10.1007\/s12032-011-0129-0"},{"key":"2025092509182442000_69.11.1017.33","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2014.56"},{"key":"2025092509182442000_69.11.1017.34","doi-asserted-by":"publisher","DOI":"10.1016\/S0145-2126(00)00065-5"},{"key":"2025092509182442000_69.11.1017.35","doi-asserted-by":"publisher","DOI":"10.1007\/BF02982021"},{"key":"2025092509182442000_69.11.1017.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.leukres.2003.10.013"},{"key":"2025092509182442000_69.11.1017.37","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2010.198"},{"key":"2025092509182442000_69.11.1017.38","first-page":"1921","article-title":"Prognostic significance of survivin expression in diffuse large B-cell lymphomas","volume":"96","author":"Adida","year":"2000","journal-title":"Blood"},{"key":"2025092509182442000_69.11.1017.39","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2403281"},{"key":"2025092509182442000_69.11.1017.40","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63140-9"},{"key":"2025092509182442000_69.11.1017.41","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2004.10.172"},{"key":"2025092509182442000_69.11.1017.42","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-11-190801"},{"key":"2025092509182442000_69.11.1017.43","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-04-280420"},{"key":"2025092509182442000_69.11.1017.44","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.10.7337"},{"key":"2025092509182442000_69.11.1017.45","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4401908"},{"key":"2025092509182442000_69.11.1017.46","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M507611200"},{"key":"2025092509182442000_69.11.1017.47","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01647-05"},{"key":"2025092509182442000_69.11.1017.48","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1205353"},{"key":"2025092509182442000_69.11.1017.49","doi-asserted-by":"publisher","DOI":"10.1016\/S0301-472X(01)00780-9"},{"key":"2025092509182442000_69.11.1017.50","doi-asserted-by":"publisher","DOI":"10.1269\/jrr.43.353"},{"issue":"3","key":"2025092509182442000_69.11.1017.51","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1242\/jcs.108.3.1287","article-title":"In vitro p53 and\/or Rb antisense oligonucleotide treatment in association with growth factors induces the proliferation of peripheral hematopoietic progenitors","volume":"108","author":"Mahdi","year":"1995","journal-title":"J Cell Sci"},{"key":"2025092509182442000_69.11.1017.52","doi-asserted-by":"publisher","DOI":"10.1002\/stem.140330"},{"key":"2025092509182442000_69.11.1017.53","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2011.10.006"},{"key":"2025092509182442000_69.11.1017.54","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00028.2012"},{"key":"2025092509182442000_69.11.1017.55","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1012718"},{"key":"2025092509182442000_69.11.1017.56","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.22216"},{"key":"2025092509182442000_69.11.1017.57","doi-asserted-by":"publisher","DOI":"10.3109\/10428194.2012.745527"},{"key":"2025092509182442000_69.11.1017.58","first-page":"194","article-title":"Evaluation of bone marrow megakaryocyte ploidy distributions in persons with normal and abnormal platelet counts","volume":"111","author":"Mazur","year":"1988","journal-title":"J Clin Lab Med"},{"key":"2025092509182442000_69.11.1017.59","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2005.03.189"},{"key":"2025092509182442000_69.11.1017.60","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M801923200"},{"key":"2025092509182442000_69.11.1017.61","doi-asserted-by":"publisher","DOI":"10.1053\/j.seminhematol.2010.03.006"},{"key":"2025092509182442000_69.11.1017.62","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20110750"},{"key":"2025092509182442000_69.11.1017.63","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-12-398834"},{"key":"2025092509182442000_69.11.1017.64","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0035631"},{"key":"2025092509182442000_69.11.1017.65","doi-asserted-by":"publisher","DOI":"10.3109\/10428199509059664"},{"key":"2025092509182442000_69.11.1017.66","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.32.2446"},{"key":"2025092509182442000_69.11.1017.67","doi-asserted-by":"publisher","DOI":"10.1007\/s00432-012-1195-1"},{"key":"2025092509182442000_69.11.1017.68","doi-asserted-by":"publisher","DOI":"10.1007\/s40259-013-0058-x"},{"key":"2025092509182442000_69.11.1017.69","doi-asserted-by":"crossref","first-page":"4213","DOI":"10.1158\/1078-0432.CCR-14-3251","article-title":"Inhibition of survivin with YM155 induces durable tumour response in anaplastic thyroid cancer","volume":"21","author":"Mehta","year":"2015","journal-title":"Cancer Clin Res"},{"key":"2025092509182442000_69.11.1017.70","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-04-569327"},{"key":"2025092509182442000_69.11.1017.71","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2013.10.018"},{"key":"2025092509182442000_69.11.1017.72","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-15-0475"}],"container-title":["Journal of Clinical Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jclinpath-2016-203625","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T16:18:36Z","timestamp":1758817116000},"score":1,"resource":{"primary":{"URL":"https:\/\/jcp.bmj.com\/lookup\/doi\/10.1136\/jclinpath-2016-203625"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,4,8]]},"references-count":72,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2016,10,19]]},"published-print":{"date-parts":[[2016,11]]}},"alternative-id":["10.1136\/jclinpath-2016-203625"],"URL":"https:\/\/doi.org\/10.1136\/jclinpath-2016-203625","relation":{},"ISSN":["0021-9746","1472-4146"],"issn-type":[{"type":"print","value":"0021-9746"},{"type":"electronic","value":"1472-4146"}],"subject":[],"published":{"date-parts":[[2016,4,8]]}}}