Ruxolitinib significantly enhances in vitro apoptosis in Hodgkin lymphoma and primary mediastinal B-cell lymphoma and survival in a lymphoma xenograft murine model
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Sanghoon Lee1,2,*, Tishi Shah1,*, Changhong Yin1, Jessica Hochberg1, Janet Ayello1, Erin Morris1, Carmella van de Ven1 and Mitchell S. Cairo1,2,3
1Department of Pediatrics, New York Medical College, Valhalla, NY 10595, USA
2Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 10595, USA
3Department of Medicine, Pathology, Microbiology and Immunology New York Medical College, Valhalla, NY 10595, USA
*These authors contributed equally to this work
Mitchell S. Cairo, email: [email protected]
Keywords: ruxolitinib; survival; Hodgkin lymphoma; primary mediastinal B-cell lymphoma
Received: November 16, 2017 Accepted: January 09, 2018 Published: January 18, 2018
Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBL) share similar molecular features by gene expression profiling. Frequent gains of chromosome 9p exhibit higher Janus Kinase 2 (JAK2) transcript levels with increased JAK2 activity, suggesting aberrant activity of JAK2 and STAT pathways. This signaling pathway alteration may in part play an important role in the pathogenesis and/or chemoradiotherapy resistance in HL and PMBL. Ruxolitinib is a potent and selective JAK1/JAK2 inhibitor, with activity against myeloproliferative neoplasms (MPNs) including those harboring the JAK2V617F mutation. We investigated the in vitro and in vivo efficacy of ruxolitinib and changes in downstream signaling pathways in HL and PMBL. We demonstrated that ruxolitinib significantly inhibited STAT signaling in both HL and PMBL with constitutively active JAK2 signaling. We also observed that ruxolitinib significantly induced in vitro anti-proliferative effects (p < 0.05) and increased programmed cell death (p < 0.05) against both HL and PMBL cells. Importantly, ruxolitinib significantly inhibited tumor progression by bioluminescence (p < 0.05) and significantly improved survival in HL (p = 0.0001) and PMBL (p < 0.0001) xenograft NSG mice. Taken altogether, these studies suggest that ruxolitinib may be a potential adjuvant targeted agent in the therapeutic approach in patients with high risk HL and PMBL.
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