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Although the molecular pathogenesis of <jats:italic>CALR<\/jats:italic> mutations leading to MPNs has been studied using <jats:italic>in vitro<\/jats:italic> cell lines models, how mutant CALR may affect developmental hematopoiesis remains unknown. Here we took advantage of the zebrafish model to examine the effects of mutant CALR on early hematopoiesis and model human <jats:italic>CALR<\/jats:italic>-mutated MPNs. We identified three zebrafish genes orthologous to human <jats:italic>CALR<\/jats:italic>, referred to as <jats:italic>calr<\/jats:italic>, <jats:italic>calr3a<\/jats:italic> and <jats:italic>calr3b<\/jats:italic>. The expression of CALR-del52 and CALR-ins5 mutants caused an increase in the hematopoietic stem\/progenitor cells followed by thrombocytosis without affecting normal angiogenesis. The expression of CALR mutants also perturbed early developmental hematopoiesis in zebrafish. Importantly, morpholino knockdown of <jats:italic>mpl<\/jats:italic> but not <jats:italic>epor<\/jats:italic> or <jats:italic>csf3r<\/jats:italic> could significantly attenuate the effects of mutant CALR. Furthermore, the expression of mutant CALR caused jak-stat signaling activation in zebrafish that could be blocked by JAK inhibitors (ruxolitinib and fedratinib). These findings showed that mutant CALR activates jak-stat signaling through an mpl-dependent mechanism to mediate pathogenic thrombopoiesis in zebrafish, and illustrated that the signaling machinery related to mutant CALR tumorigenesis are conserved between human and zebrafish.<\/jats:p>","DOI":"10.1038\/bcj.2016.83","type":"journal-article","created":{"date-parts":[[2016,10,7]],"date-time":"2016-10-07T13:26:37Z","timestamp":1475846797000},"page":"e481-e481","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Expression of CALR mutants causes mpl-dependent thrombocytosis in zebrafish"],"prefix":"10.1038","volume":"6","author":[{"given":"K-H","family":"Lim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y-C","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y-H","family":"Chiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H-C","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C-Y","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C-S","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W-T","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Gon-Shen Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W-C","family":"Chou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y-Y","family":"Kuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,10,7]]},"reference":[{"key":"BFbcj201683_CR1","doi-asserted-by":"publisher","first-page":"937","DOI":"10.1182\/blood-2009-03-209262","volume":"114","author":"JW Vardiman","year":"2009","unstructured":"Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A et al. 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