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.
journal_name
Am J Hematoljournal_title
American journal of hematologyauthors
Garbati MR,Welgan CA,Landefeld SH,Newell LF,Agarwal A,Dunlap JB,Chourasia TK,Lee H,Elferich J,Traer E,Rattray R,Cascio MJ,Press RD,Bagby GC,Tyner JW,Druker BJ,Dao KHdoi
10.1002/ajh.24245subject
Has Abstractpub_date
2016-02-01 00:00:00pages
211-9issue
2eissn
0361-8609issn
1096-8652journal_volume
91pub_type
杂志文章abstract::The relationship between thrombocytopenia and the level of anticardiolipin antibodies (aCL) and/or the existence of lupus anticoagulant (LA) ware studied in 146 patients with systemic lupus erythematosus (SLE). These patients were divided into six groups: A, those LA positive with a high level of aCL (>10 U/ml) (10 ca...
journal_title:American journal of hematology
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journal_title:American journal of hematology
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