@article{f5ff79ad4c5647278dc024b32049fcc6,
title = "Mutant calreticulin-expressing cells induce monocyte hyperreactivity through a paracrine mechanism",
abstract = "Mutations in the calreticulin gene (CALR) were recently identified in approximately 70-80% of patients with JAK2-V617F-negative essential thrombocytosis and primary myelofibrosis. All frameshift mutations generate a recurring novel C-terminus. Here we provide evidence that mutant calreticulin does not accumulate efficiently in cells and is abnormally enriched in the nucleus and extracellular space compared to wildtype calreticulin. The main determinant of these findings is the loss of the calcium-binding and KDEL domains. Expression of type I mutant CALR in Ba/F3 cells confers minimal IL-3-independent growth. Interestingly, expression of type I and type II mutant CALR in a nonhematopoietic cell line does not directly activate JAK/STAT signaling compared to wildtype CALR and JAK2-V617F expression. These results led us to investigate paracrine mechanisms of JAK/STAT activation. Here we show that conditioned media from cells expressing type I mutant CALR exaggerate cytokine production from normal monocytes with or without treatment with a toll-like receptor agonist. These effects are not dependent on the novel C-terminus. These studies offer novel insights into the mechanism of JAK/STAT activation in patients with JAK2-V617F-negative essential thrombocytosis and primary myelofibrosis.",
author = "Garbati, {Michael R.} and Welgan, {Catherine A.} and Landefeld, {Sally H.} and Newell, {Laura F.} and Anupriya Agarwal and Dunlap, {Jennifer B.} and Chourasia, {Tapan K.} and Hyunjung Lee and Johannes Elferich and Elie Traer and Rogan Rattray and Cascio, {Michael J.} and Press, {Richard D.} and Bagby, {Grover C.} and Tyner, {Jeffrey W.} and Druker, {Brian J.} and Dao, {Kim Hien T.}",
note = "Funding Information: We acknowledge Jakki Martinez, Drs. Stefanie Kaech Petrie, Kevin Watanabe-Smith, and Julia Maxson for their advice and technical support and Drs. Brian Ruffell and Lisa Coussens for use of the macro and Aperio ScanScope AT microscope. This work was largely supported by grants supporting KTD, who receives support from the OHSU Knight Cancer Institute and the National Institutes of Health, National Heart, Lung and Blood Institute (1K08HL111280). This work was partially supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR000128. LFN is supported by a grant from Office of Research in Women?s Health and the National Institute of Child Health and Human Development, Oregon BIRCWH Award Number 2K12HD043488. AA is supported by a National Cancer Institute Career Development Award (4 R00CA151670-03). BJD is supported by the Howard Hughes Medical Institute. Funding Information: We acknowledge Jakki Martinez, Drs. Stefanie Kaech Petrie, Kevin Watanabe-Smith, and Julia Maxson for their advice and technical support and Drs. Brian Ruffell and Lisa Coussens for use of the macro and Aperio ScanScope AT microscope. This work was largely supported by grants supporting KTD, who receives support from the OHSU Knight Cancer Institute and the National Institutes of Health, National Heart, Lung and Blood Institute (1K08HL111280). This work was partially supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR000128. LFN is supported by a grant from Office of Research in Women{\textquoteright}s Health and the National Institute of Child Health and Human Development, Oregon BIRCWH Award Number 2K12HD043488. AA is supported by a National Cancer Institute Career Development Award (4 R00CA151670-03). BJD is supported by the Howard Hughes Medical Institute. Publisher Copyright: {\textcopyright} 2016 Wiley Periodicals, Inc. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.",
year = "2016",
month = feb,
day = "1",
doi = "10.1002/ajh.24245",
language = "English (US)",
volume = "91",
pages = "211--219",
journal = "American Journal of Hematology",
issn = "0361-8609",
publisher = "Wiley-Liss Inc.",
number = "2",
}