Cooperative Epigenetic Modulation by Cancer Amplicon Genes

Amplification of a ~2.5 megabase region on chromosome 9p24 is frequent in both primary mediastinal B-cell lymphoma (PMBL) and Hodgkin's lymphoma (HL). To identify the oncogenic genes in this interval, we created a RNA interference library targeting amplicon genes. A genetic screen using this library identified three genes that are essential for the proliferation and survival of PMBL and HL lines with this amplicon, which encode the kinase JAK2, the histone demethylase JMJD2C and a gene of unknown function, RANBP6. Inhibition of JAK2 and JMJD2C cooperated in killing these lymphomas and in remodeling their chromatin by globally increasing trimethylation of lysine 9 on histone H3 (H3K9me3) and heterochromatin formation. JAK2 and JMJD2C inhibition silenced MYC and its target genes, which coincided with an increase in H3K9me3 and the heterochromatin protein HP1alpha at the MYC locus. We conclude that amplification of JAK2 and JMJD2C cooperatively reprograms the PMBL and HL epigenome, sustaining their survival and proliferation. Signal from untreated shRNA cells or DMSO control cells (Cy3) was compared to 4 dox-treated JAK2 shRNA cells, 4 dox-treated JMJD2C shRNA cells, or 8 JAK2 inhibitor-treated cells (Cy5).