Abstract
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.
Highlights
Hodgkin lymphoma (HL) and primary mediastinal large B-cell lymphoma (PMBL) are two of the most common malignancies among adolescents and young adults (AYA)
Considered a mature B-cell lymphoma, we have identified that children and adolescents with newly diagnosed primary mediastinal B-cell lymphoma (PMBL) have a significantly decreased eventfree survival (EFS) compared to children and adolescents with other forms of diffuse large B-cell lymphoma (DLBCL) treated with similar therapy [16]
We observed that increasing concentrations of ruxolitinib (10-100 nM) for 24 h significantly inhibited downstream active phosphorylated STAT3 (p-STAT3, p < 0.005 at 10 nM, and p < 0.0005 at 25 - 100 nM) and phosphorylated STAT5 (p-STAT5, p < 0.005 at 10 nM, p < 0.0005 at 25 nM, and p < 0.0001 at 50 and 100 nM) in a dose-dependent manner in HDLM-2 cells (Figure 1A and 1C), whereas, total STAT3 and STAT5 levels remained unchanged at the concentrations up to 100 nM (Figure 1B and 1D)
Summary
Hodgkin lymphoma (HL) and primary mediastinal large B-cell lymphoma (PMBL) are two of the most common malignancies among adolescents and young adults (AYA). HL represents approximately 4–5% of all cancers in children younger than 15 years of age, HL is the most common cancer in the 15–35 years AYA group, with an incidence of about 16% [4]. The prognosis is excellent in AYA with HL, with 10 year overall survival rates approximately 85–95% [5]. There are significant late effects secondary to chemo-radiotherapy in patients with HL, including cardiac and pulmonary toxicity, infertility and increased risk of www.impactjournals.com/oncotarget secondary malignancy, which affect the long-term eventfree survival (EFS) especially in AYA [8, 9]. New targeted agents are needed to avoid late effects in HL and improve the outcomes in patients with high risk of relapse/progression
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