Expression of a non-DNA-binding isoform of Helios induces T-cell lymphoma in mice.
Helios is a zinc-finger protein belonging to the Ikaros family of transcriptional regulators. It is expressed, along with Ikaros, throughout early stages of thymocyte development where it quantitatively associates with Ikaros through C-terminal zinc-finger domains that mediate heterodimerization 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 progenitor cells of reconstituted mice. Constitutive expression of full-length Helios resulted in an inhibition of T-cell development at the double-negative stage within the thymus. Although expression of the DNA-binding mutant of Helios did not contribute to developmental abnormalities at early times after transplantation, 60% of animals that expressed the Helios DNA-binding mutant developed an aggressive and transplantable T-cell lymphoma 4 to 10 months after transplantation. These results demonstrate a vital function for Helios in maintaining normal homeostasis of developing T cells and formally show that non-DNA-binding isoforms of Helios are lymphomagenic if aberrantly expressed within the T-cell lineage.
Zhang
Zheng
Z
Department of Microbiology, Division of Developmental and Clinical Immunology, University of Alabama at Birmingham, AL, USA.
Swindle
C Scott
CS
Bates
John T
JT
Ko
Rose
R
Cotta
Claudiu V
CV
Klug
Christopher A
CA
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D007694:Killer Cells, Natural / Q000166:cytology / Q000378:metabolism; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000145:classification / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D020033:Protein Isoforms; D014157:Transcription Factors; C491746:Zfpn1a2 protein, mouse