Epigenetic Gene Regulation By JAK1 In Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) grows rapidly and represents 30% to 40% of newly diagnosed lymphomas. The most aggressive subtype, termed activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL), is dependent on the autocrine cytokines IL-6 or IL-10 for survival. Our recent work has demonstrated that secretion of the cytokines in these lymphoma cells is mediated by aberrant NF-κB activation, including gain-of-function mutations in the MYD88 gene. In this study, we will dissect the molecular mechanisms of the cytokine signaling in lymphomagenesis.

We have evidence that the Janus kinase downstream of the cytokine signaling is JAK1. I obtained a surprising result demonstrating that JAK1 localization is largely nuclear, and that JAK1 can modify the nuclear histone protein H3 through phosphorylating tyrosine 41 (H3Y41). We and others have discovered that this chromatin modification can be initiated by the homologue JAK2 in leukemia cells as well as in primary mediastinal and Hodgkin lymphoma cells. H3Y41 phosphorylation displaces the inhibitory protein HP1 from chromatin and activates gene transcription. Genome-wide mapping by Chip-Seq using antibodies specific for H3Y41 phosphorylation identified 2,582 candidate genes modified by activated JAK1 in ABC DLBCL cells. These include important oncogenes such as MYC, key NF-kB pathway genes, and AP1 genes whose function is not appreciated in this lymphoma. Given that inhibition of some of these genes by RNA interference or by pharmaceutical inhibitors is lethal to cultured ABC DLBCL cells, they will be considered potential molecular targets for therapeutic development.