title: Adult T-cell leukemia cells are characterized by abnormalities of Helios expression that promote T cell growth.
abstract: Molecular abnormalities involved in the multistep leukemogenesis of adult T-cell leukemia (ATL) remain to be clarified. Based on our integrated database, we focused on the expression patterns and levels of Ikaros family genes, Ikaros, Helios, and Aiolos, in ATL patients and HTLV-1 carriers. The results revealed profound deregulation of Helios expression, a pivotal regulator in the control of T-cell differentiation and activation. The majority of ATL samples (32/37 cases) showed abnormal splicing of Helios expression, and four cases did not express Helios. In addition, novel genomic loss in Helios locus was observed in 17/168 cases. We identified four ATL-specific short Helios isoforms and revealed their dominant-negative function. Ectopic expression of ATL-type Helios isoform as well as knockdown of normal Helios or Ikaros promoted T-cell growth. Global mRNA profiling and pathway analysis showed activation of several signaling pathways important for lymphocyte proliferation and survival. These data provide new insights into the molecular involvement of Helios function in the leukemogenesis and phenotype of ATL cells, indicating that Helios deregulation is one of the novel molecular hallmarks of ATL.
authors.affiliation: Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Asanuma
authors.forename: Makoto
authors.initials: M
authors.lastname: Yamagishi
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Kawanami
authors.forename: Kazumi
authors.initials: K
authors.lastname: Nakano
authors.forename: Aiko
authors.initials: A
authors.lastname: Sato-Otsubo
authors.forename: Satsuki
authors.initials: S
authors.lastname: Muto
authors.forename: Masashi
authors.initials: M
authors.lastname: Sanada
authors.forename: Tadanori
authors.initials: T
authors.lastname: Yamochi
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Atae
authors.initials: A
authors.lastname: Utsunomiya
authors.forename: Masako
authors.initials: M
authors.lastname: Iwanaga
authors.forename: Kazunari
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Kaoru
authors.initials: K
authors.lastname: Uchimaru
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Toshiki
authors.initials: T
authors.lastname: Watanabe
mesh_terms: D048708:Cell Growth Processes / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D005091:Exons; D057809:HEK293 Cells; D006367:HeLa Cells; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051740:Ikaros Transcription Factor / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology*
chemical_list: C111431:IKZF2 protein, human; C106285:IKZF3 protein, human; D020033:Protein Isoforms; D051740:Ikaros Transcription Factor