CELL BIOLOGY AND SIGNALING

Ikaros, a DNA-binding protein also known as Ikaros family zinc finger protein 1 (IKZF1), was initially shown to function critically in hematopoietic differentiation. Deletion or mutation of Ikaros has been associated with lymphoblastic, as well as acute and chronic myelogenous leukemias demonstrating that Ikaros can act as a tumor suppressor. Ikaros is predominantly expressed in a variety of tissue including the brain, suggesting that Ikaros may be involved in the physiological functions of glial growth. Other recent studies have shown that Ikaros can regulate the transition of neural progenitor cells to postmitotic neurons which eventually differentiate into glial cells. Deregulation of glial development and/or growth has been shown to initiate glioblastoma (GBM) growth suggesting that Ikaros may be involved in GBM tumorigenesis. The goal of this study was to determine if Ikaros plays an important role in glial tumorigenesis. Analysis using the TCGA and Rembrandt databases demonstrated that decreased expression of Ikaros leads to worse prognosis in GBM patients (P , 0.01). In addition, the Ikaros promoter was found to be hypermethylated (85% of samples) in GBM samples suggesting that inhibition of Ikaros may contribute to glial tumorigenesis. To determine if Ikaros is involved in glial tumorigenesis we generated stable GBM cell lines that were transduced with HA-Ikaros. Enhanced expression of Ikaros resulted in a 3-to 4-fold reduction in proliferation and a 2-to 3-fold reduction in colony formation. In addition, exogenous expression of Ikaros inhibited the migration of GBM cells suggesting that Ikaros may also be involved in the invasiveness of glial cancers. Together our data suggests that Ikaros may play an important role in suppressing glial tumor formation and may be a novel biomarker for GBMs.

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