Homozygous deletions of the p15 (MTS2) and p16 (CDKN2/MTS1) genes in adult T-cell leukemia

Hatta, Yoshihiro; Hirama, Toshiyasu; Cw, Miller; Yamada, Yasuaki; Tomonaga, Masao; Koeffler, H. Phillip

doi:10.1182/blood.v85.10.2699.bloodjournal85102699

Cited by 153 publications

(39 citation statements)

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“…Previous studies have demonstrated that the CDKN2 gene is inactivated by a variety of mechanisms Merlo et al, 1995). In ATL, one recent study reported frequent homozygous deletions and no point mutation (Hatta et al, 1995). In the present study, we also found some homozygous deletions.…”

Section: Discussionsupporting

confidence: 86%

“…The CDKN2 gene alterations frequently occurred in acute-type ATL in this study (6/19, 31 . 6%), and has also been previously reported (Hatta et al, 1995), suggesting that the CDKN2 gene is involved in the late stage of ATL leukaemogenesis.…”

Section: Discussionsupporting

confidence: 71%

“…Adult T-cell leukaemia (ATL) is a mature T-cell malignancy associated with human T-cell leukaemia virus type 1 (HTLV-1) (Uchiyama et al, 1977;Franchini, 1995). Information on CDKN2 gene alterations in ATL has previously been very limited (Hatta et al, 1995). In this study, to evaluate changes in the CDKN2 gene, and to determine whether this gene plays an important role in ATL progression, we performed Southern blot analysis, polymerase chain reaction-mediated singlestrand conformation polymorphism (PCR-SSCP), and direct sequence analysis of the CDKN2 gene.…”

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confidence: 99%

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The CDKN2 gene alterations in various types of adult T‐cell leukaemia

et al. 1996

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The CDKN2 gene, encoding the cyclin-dependent kinase-4 inhibitor p16, is a putative tumour-suppressor gene because it is frequently altered in many malignant tumours. We analysed the CDKN2 gene in 44 cases of adult T-cell leukaemia (ATL) by Southern blot analysis, polymerase chain reaction-mediated single-strand conformation polymorphism (PCR-SSCP) analysis, and direct sequencing. Southern blot analysis detected a homozygous deletion of the CDKN2 gene in 5/44 patients (11.4%). Mutational analysis by the PCR-SSCP method and direct sequencing showed one nonsense mutation at codon 72 (nucleotide 232), and two missense mutations at codon 43 (nucleotide 146) and codon 97 (nucleotide 309, 3/44, 6.8%). Therefore we found changes in the CDKN2 gene, including point mutations, in 18.2% of the patients with ATL. Interestingly, most of these patients had acute type ATL. Our results suggest that the CDKN2 gene is inactivated not only by homozygous deletion but also by point mutation, and these alterations contribute to the aggressiveness of ATL.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 71%

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confidence: 99%

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The CDKN2 gene alterations in various types of adult T‐cell leukaemia

et al. 1996

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“…[31][32][33] Deletion of the genes encoding the cyclindependent kinase inhibitors p15INK4B and/or p16INK4A, and repressed expression of the p16INK4A gene by methylation, were found in ATL and correlated with the ATL subtype. [34][35][36] In addition, the deletion of p15INK4B and/ or p16INK4A during disease progression was also reported in ATL. 34) Another tumor suppressor gene, p53, is also known to be involved in cell cycle regulation.…”

Section: Discussionmentioning

confidence: 99%

Possible Involvement of Interferon Regulatory Factor 4 (IRF4) in a Clinical Subtype of Adult T‐Cell Leukemia

Imaizumi

Kohno

Yamada

et al. 2001

Japanese Journal of Cancer Research

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Interferon regulatory factor (IRF) 4 is the lymphoid-specific transcription factor that is required for the proliferation of mitogen-activated T cells. IRF4 has been suggested to be involved in tumorigenesis because the overexpression of IRF4 caused the transformation of Rat-1 fibroblasts in vitro. Here, we show that IRF4 is constitutively expressed in adult T-cell leukemia (ATL)-derived cell lines, which were infected with human T-cell leukemia virus type-I, but hardly expressed the trans-activator protein, Tax. Similarly, constitutive expression of IRF4 was demonstrated in freshly isolated peripheral blood mononuclear cells (PBMC) from patients with either acute or chronic ATL. However, the high-level expression of IRF4 was specifically associated with acute ATL. With mitogen-activated PBMC from healthy donors, cell cycle analyses revealed that the induction of IRF4 occurred prior to cell cycle progression and the cells that had entered the cell cycle were predominantly IRF4-positive cells. In addition, ectopic expression of IRF4 in Rat-1 fibroblasts increased the S and G2/M phase population significantly. Taken together, our results indicate that IRF4 is involved in the pathogenesis of ATL through its positive effect on the cell cycle, and that IRF4 can be used as a molecular marker of clinical subtype in ATL.

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“…7 The prototype of ATL is an aggressive T-cell neoplasm, but four clinical subtypes have been identified (latent, chronic, lymphoma and acute), 8 and leukemic cells are believed to evolve clonally or progress from chronic-to acute-type ATL with disease aggressiveness. 9 While acutetype ATL cells have more deregulated and/or altered forms of oncoproteins as well as tumor-suppressor proteins (p15, p16, p53), [10][11][12][13] the phenotypic characterization of ATL cells has revealed that transcription of the human leukocyte antigen (HLA)-DR gene is reduced in some acute-type ATL cells. 4 We previously established a B-dendritic cell line, HBM-Noda, and characterized its phenotype and functional characteristics.…”

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Human leukocyte antigen‐class II‐negative long‐term cultured human T‐cell leukemia virus type‐I‐infected T‐cell lines with progressed cytological properties significantly induce superantigen‐dependent normal T‐cell proliferation

Nagasaki¹,

Zhang²,

Morikawa

et al. 2005

Pathology International

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While most human T-cell leukemia virus type-I (HTLV-I)-infected T cells express abundant class II antigens, some aggressive-type adult T-cell leukemia (ATL) cells lose their expression. To investigate the significance of the class II antigen of HTLV-I infected cells, the progressiveness of HTLV-I-infected long-term cultured T-cell lines was evaluated, and then their antigen-presenting capacity was examined using a superantigen, staphylococcus enterotoxin B (SEB). Among the cell lines derived from peripheral blood, HPB-ATL-T (ATL-T), HPB-ATL-2 (ATL-2) and HPB-ATL-O were more progressed than Tax exclusively expressing HPB-CTL-I (CTL-I), because the former deleted p16 gene (polymerase chain reaction (PCR)) and strongly transcribed survivin (reverse transcriptase-PCR). Notably, interferon gamma-independent loss of class II expression of ATL-T and ATL-2 was found. In antigen-presenting experiments, however, both cell lines induced SEB-dependent significant T-cell proliferation estimated by [(3)H] thymidine uptake. No class II-re-expressed ATL-2 cells were observed in the SEB-presenting cultures by indirect immunofluorescence, and only minimum inhibition of SEB-dependent T-cell response by anti-human leukocyte antigen (HLA)-DR monoclonal antibody was observed. These findings suggest that both ATL-T and ATL-2 very effectively present SEB to T cells less dependently on class II molecules. These less immunogenic leukemic cells of aggressive ATL may contribute to disease aggression.

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Homozygous deletions of the p15 (MTS2) and p16 (CDKN2/MTS1) genes in adult T-cell leukemia

Cited by 153 publications

References 0 publications

The CDKN2 gene alterations in various types of adult T‐cell leukaemia

The CDKN2 gene alterations in various types of adult T‐cell leukaemia

Possible Involvement of Interferon Regulatory Factor 4 (IRF4) in a Clinical Subtype of Adult T‐Cell Leukemia

Human leukocyte antigen‐class II‐negative long‐term cultured human T‐cell leukemia virus type‐I‐infected T‐cell lines with progressed cytological properties significantly induce superantigen‐dependent normal T‐cell proliferation

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