Ikaros, encoded by the IKZF1 gene, is a pivotal transcription factor whose expression and utilization is dynamically altered during hematopoietic development. However, the molecular mechanisms controlling the transcription of the IKZF1 gene are unclear in lung cancer cell lines. Here we show the role of Ikaros in a cohort of grade IIIA lung cancer patients, with particular emphasis on its relationship with clinical outcomes and expression levels. The expression levels of Ikaros were positively correlated with the prognosis in the lung cancer patients. We also demonstrated that Ikaros expression is ectopically activated in a panel of lung cancer cell lines primarily through demethylation of its promoter. Moreover, gain-of-function experiments revealed that Ikaros inhibits migration and invasion of lung cancer cells in vitro. Our results thus shed light on how Ikaros can act as a lineage competency factor to facilitate lung cancer progression. Anat Rec, 296:907–913, 2013. © 2013 Wiley Periodicals, Inc.