IL-15 induces aneuploidy and global DNA hypermethylation in large granular lymphocytes.
Major finding: IL-15 induces aneuploidy and global DNA hypermethylation in large granular lymphocytes.
Clinical relevance: Liposomal bortezomib led to 100% survival in mice with large granular lymphocyte leukemia.
Impact: Altered cytokine expression can directly initiate cancer by inducing genetic and epigenetic changes.
The release of proinflammatory cytokines can stimulate cellular changes and increase the risk of oncogenic transformation, but mechanisms by which cytokines might directly cause cancer remain uncharacterized. Overexpression of interleukin (IL)-15, a cytokine required for large granular lymphocyte (LGL) development and homeostasis, causes leukemia in transgenic mice and is observed in human LGL leukemia, an aggressive cancer with no curative treatment. Mishra and colleagues demonstrated that IL-15 plays a direct role in leukemic transformation by showing that high IL-15 levels promote robust growth of wild-type mouse LGLs in vitro and that adoptive transfer of IL-15-treated LGLs into immunodeficient mice leads to fatal LGL leukemia. IL-15 induced a high degree of aneuploidy in LGLs that was associated with MYC- and NF-κB–dependent upregulation of Aurora kinases and concurrent centrosomal aberrations. Additionally, global DNA methylation increased in LGLs exposed to IL-15 due to DNA methyltransferase 3B upregulation, which occurred via MYC-, HDAC1-, and NF-κB–dependent repression of its negative regulator, microRNA (miR)-29b. Importantly, these observations were confirmed in primary cells from patients with aggressive LGL leukemia, suggesting that IL-15 plays a similar role in initiation of the human disease. Given the apparent role of NF-κB in IL-15–induced chromosomal instability and DNA hypermethylation, the authors tested the efficacy of a liposomal preparation of bortezomib, a proteasome inhibitor with anticancer activity mediated partly through NF-κB inhibition that had improved pharmacodynamic characteristics in mice compared with the naked compound. Strikingly, all immunodeficient mice engrafted with a lethal dose of IL-15–induced LGL leukemic blasts that were treated with liposomal bortezomib survived, with a significant reduction of disease burden and no evidence of toxicity. These findings thus provide mechanistic insight into how proinflammatory cytokines can directly initiate cancer and a strong rationale for the evaluation of liposomal bortezomib in patients with LGL leukemia.