Abstract
Natural killer/T-cell lymphoma (NKTCL) is an aggressive non-Hodgkin lymphoma that has been facing limited success with conventional treatments, urging for the discovery of alternative strategies. Recent studies including ours have revealed that EZH2 and JAK-STAT signalling pathways are key contributors to NKTCL pathogenesis. In particular, we found that EZH2 is overexpressed and directly transcriptionally activates the CCND1 gene to confer growth advantage. CCND1 codes for cyclin D1, which complexes with CDK4/6 to promote G1 to S phase transition. Therefore in this study we investigated whether inhibiting both JAK1/2 and CDK4/6, using LEE011 and ruxolitinib respectively is effective in NKTL. We first demonstrate that separate LEE011 and ruxolitinib treatment is sufficient to cause growth inhibition of NKTCL cells. More importantly, we found that there is synergistic growth inhibitory effects on NKTCL cells with combination treatment of LEE011 and ruxolitinib. The results obtained shows that the targeting of both CDK4/6 and JAK1/2 are promising to develop better treatment alternatives for NKTCL.
Highlights
Natural killer/T-cell lymphoma (NKTCL) is an aggressive type of non-Hodgkin lymphoma characterised by a clonal proliferation of NK or T-cells, and patients often have poor survival rates [1, 2]
Growth inhibition on NKTCL cell lines was achieved with independent CDK4/6 and JAK1/2 inhibition
To evaluate growth inhibitory efficacy of CDK4/6 and JAK1/2 inhibition separately, the NKTCL cell lines were treated to a range of LEE011 and ruxolitinib concentrations
Summary
Natural killer/T-cell lymphoma (NKTCL) is an aggressive type of non-Hodgkin lymphoma characterised by a clonal proliferation of NK or T-cells, and patients often have poor survival rates [1, 2]. The activated STAT3 status was subsequently found to be due to STAT3 activating mutations and/or the loss of receptor-type tyrosine-protein phosphatase κ [7, 12, 13] and could be brought down to normal phosphorylated STAT3 levels upon JAK2 inhibition [7, 13]. These findings suggest that the STAT3 pathway could be a promising target for alternative NKTCL treatment
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