NEOPLASIA Expression of a non–DNA-binding isoform of Helios induces T-cell lymphoma

Helios is a zinc-finger protein belonging to the Ikaros family of transcriptional regu-lators. It is expressed, along with Ikaros, throughout early stages of thymocyte development where it quantitatively asso-ciates with Ikaros through C-terminal zinc-finger domains that mediate heterodimer-ization between Ikaros family members. To understand the role of Helios in T-cell development, we used a retroviral vector to express full-length Helios or a Helios isoform that lacked the N-terminal DNA-binding domain in hematopoietic progeni-tor cells of reconstituted mice. Constitu-tive expression of full-length Helios resulted in an inhibition of T-cell develop-ment at the double-negative stage within the thymus. Although expression of the DNA-binding mutant of Helios did not contribute to developmental abnormali-ties at early times after transplantation, 60 % of animals that expressed the Helios DNA-binding mutant developed an ag-gressive and transplantable T-cell lym-phoma 4 to 10 months after transplanta-tion. These results demonstrate a vital function for Helios in maintaining normal homeostasis of developing T cells and formally show that non–DNA-binding iso-forms of Helios are lymphomagenic if aberrantly expressed within the T-cell lin-eage. (Blood. 2007;109:2190-2197) © 2007 by The American Society of Hematolog