title: Decreases in Ikaros activity correlate with blast crisis in patients with chronic myelogenous leukemia.
abstract: Gene targeting studies in mice have shown that the lack of Ikaros activity leads to T-cell hyperproliferation and T-cell neoplasia, establishing the Ikaros gene as a tumor suppressor gene in mice. This prompted us to investigate whether mutations in Ikaros play a role in human hematological malignancies. Reverse transcription-PCR was used to determine the relative expression levels of Ikaros isoforms in a panel of human leukemia/lymphoma cell lines and human bone marrow samples from patients with hematological malignancies. Among the cell lines examined, only BV-173, which was derived from a chronic myelogenous leukemia (CML) patient in lymphoid blast crisis, overexpressed the dominant-negative isoform, Ik-6. In 9 of 17 samples of patients in blast crisis of CML, Ikaros activity had been reduced either by drastically reducing mRNA expression (4 of 17) or by overexpressing the dominant-negative isoform Ik-6 (5 of 17). Significantly, expression of Ikaros isoforms seemed normal in chronic phase CML patients and patients with other hematological malignancies. In some cases, overexpression of the dominant-negative Ik-6 protein was confirmed by Western blot analysis, and Southern blot analysis indicated that decreases in Ikaros activity correlated with a mutation in the Ikaros locus. In summary, these findings suggest that a reduction of Ikaros activity may be an important step in the development of blast crisis in CML and provide further evidence that mutations that alter Ikaros expression may contribute to human hematological malignancies.
authors.affiliation: Department of Medicine, University of Okayama, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Nakayama
authors.forename: F
authors.initials: F
authors.lastname: Ishimaru
authors.forename: N
authors.initials: N
authors.lastname: Avitahl
authors.forename: N
authors.initials: N
authors.lastname: Sezaki
authors.forename: N
authors.initials: N
authors.lastname: Fujii
authors.forename: K
authors.initials: K
authors.lastname: Nakase
authors.forename: Y
authors.initials: Y
authors.lastname: Ninomiya
authors.forename: A
authors.initials: A
authors.lastname: Harashima
authors.forename: J
authors.initials: J
authors.lastname: Minowada
authors.forename: J
authors.initials: J
authors.lastname: Tsuchiyama
authors.forename: K
authors.initials: K
authors.lastname: Imajoh
authors.forename: T
authors.initials: T
authors.lastname: Tsubota
authors.forename: S
authors.initials: S
authors.lastname: Fukuda
authors.forename: T
authors.initials: T
authors.lastname: Sezaki
authors.forename: K
authors.initials: K
authors.lastname: Kojima
authors.forename: M
authors.initials: M
authors.lastname: Hara
authors.forename: H
authors.initials: H
authors.lastname: Takimoto
authors.forename: S
authors.initials: S
authors.lastname: Yorimitsu
authors.forename: I
authors.initials: I
authors.lastname: Takahashi
authors.forename: A
authors.initials: A
authors.lastname: Miyata
authors.forename: S
authors.initials: S
authors.lastname: Taniguchi
authors.forename: Y
authors.initials: Y
authors.lastname: Tokunaga
authors.forename: H
authors.initials: H
authors.lastname: Gondo
authors.forename: Y
authors.initials: Y
authors.lastname: Niho
authors.forename: M
authors.initials: M
authors.lastname: Harada
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001752:Blast Crisis / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D051740:Ikaros Transcription Factor; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000473:pathology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C497239:IKZF1 protein, human; D014157:Transcription Factors; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor