JAK-2 V617F mutation increases heparanase procoagulant activity.
Patients with polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF) are at increased risk of arterial and venous thrombosis. In patients with ET a positive correlation was observed between JAK-2 V617F mutation, that facilitates erythropoietin receptor signalling, and thrombotic events, although the mechanism involved is not clear. We previously demonstrated that heparanase protein forms a complex and enhances the activity of the blood coagulation initiator tissue factor (TF) which leads to increased factor Xa production and subsequent activation of the coagulation system. The present study was aimed to evaluate heparanase procoagulant activity in myeloproliferative neoplasms. Forty bone marrow biopsies of patients with ET, PV, PMF and chronic myelogenous leukaemia (CML) were immunostained to heparanase, TF and TF pathway inhibitor (TFPI). Erythropoietin receptor positive cell lines U87 human glioma and MCF-7 human breast carcinoma were studied. Heparanase and TFPI staining were more prominent in ET, PV and PMF compared to CML. The strongest staining was in JAK-2 positive ET biopsies. Heparanase level and procoagulant activity were higher in U87 cells transfected to over express JAK-2 V617F mutation compared to control and the effect was reversed using JAK-2 inhibitors (Ruxolitinib, VZ3) and hydroxyurea, although the latter drug did not inhibit JAK-2 phosphorylation. Erythropoietin increased while JAK-2 inhibitors decreased the heparanase level and procoagulant activity in U87 and MCF-7 parental cells. In conclusion, JAK-2 is involved in heparanase up-regulation via the erythropoietin receptor. The present findings may potentially point to a new mechanism of thrombosis in JAK-2 positive ET patients.
Inna
I
Kogan
Dafna
D
Chap
Ron
R
Hoffman
Elena
E
Axelman
Benjamin
B
Brenner
Yona Nadir, MD, PhD, Thrombosis and Hemostasis Unit,, Rambam Health Care Campus, Haifa, Israel, Tel.: +972 4 8453520, Fax: +972 4 8543886, E-mail: ynadir@netvision.net.il.
Yona
Y
Nadir
D001706:Biopsy; D001853:Bone Marrow / Q000187:drug effects / Q000201:enzymology*; D001856:Bone Marrow Examination; D004252:DNA Mutational Analysis; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005966:Glucuronidase / Q000378:metabolism*; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D008074:Lipoproteins / Q000378:metabolism; D061986:MCF-7 Cells; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation; D011087:Polycythemia Vera / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D055728:Primary Myelofibrosis / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017467:Receptors, Erythropoietin / Q000378:metabolism; D013920:Thrombocythemia, Essential / Q000097:blood / Q000201:enzymology / Q000235:genetics*; D014162:Transfection; D000099175:Heparanase
D005819:Genetic Markers; D005966:Glucuronidase; D053614:Janus Kinase 2; D008074:Lipoproteins; D047428:Protein Kinase Inhibitors; D017467:Receptors, Erythropoietin; D000099175:Heparanase; C051928:lipoprotein-associated coagulation inhibitor; C507924:JAK2 protein, human
Heparanase; JAK-2; coagulation; myeloproliferative