Identification of FOXO3 and PRDM1 as tumor-suppressor gene candidates in NK-cell neoplasms by genomic and functional analyses

Kennosuke Karube, Masao Nakagawa, Shinobu Tsuzuki, Ichiro Takeuchi, Keiichiro Honma, Yasuhiro Nakashima, Norio Shimizu, Young Hyeh Ko, Yasuo Morishima, Koichi Ohshima, Shigeo Nakamura, Masao Seto

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Abstract

Oligo-array comparative genomic hybridization (CGH) and gene-expression profiling of natural killer (NK) - cell neoplasms were used in an effort to delineate the molecular pathogenesis involved. Oligoarray CGH identified two 6q21 regions that were most frequently deleted (14 of 39 or 36%). One of these regions included POPDC3, PREP, PRDM1, ATG5, and AIM1, whereas the other included LACE1 and FOXO3. All genes located in these regions, except for POPDC3 and AIM1, were down-regulated in neoplastic samples, as determined by gene-expression analysis, and were therefore considered to be candidate tumor-suppressor genes. A20 and HACE1, the well-known tumor-suppressor genes located on 6q21-23, were included as candidate genes because they also demonstrated frequent genomic deletions and down-regulated expression. The Tet-Off NK cell line NKL was subsequently established for functional analyses. Seven candidate genes were transduced into Tet-Off NKL and forced re-expression was induced. Re-expression of FOXO3 and PRDM1 suppressed NKL proliferation, but this was not the case after re-expression of the other genes. This effect was confirmed using another NK cell line, SNK10. Furthermore, genomic analyses detected nonsense mutations of PRDM1 that led to functional inactivation in one cell line and one clinical sample. PRDM1 and FOXO3 are considered to play an important role in the pathogenesis of NK-cell neoplasms.

Original languageEnglish
Pages (from-to)3195-3204
Number of pages10
JournalBlood
Volume118
Issue number12
DOIs
Publication statusPublished - Sep 22 2011

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Tumor Suppressor Genes
Natural Killer Cells
Tumors
Genes
Comparative Genomic Hybridization
Cell Line
Neoplasms
Cells
Gene Expression
Gene expression
Nonsense Codon
Gene Expression Profiling

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Identification of FOXO3 and PRDM1 as tumor-suppressor gene candidates in NK-cell neoplasms by genomic and functional analyses. / Karube, Kennosuke; Nakagawa, Masao; Tsuzuki, Shinobu; Takeuchi, Ichiro; Honma, Keiichiro; Nakashima, Yasuhiro; Shimizu, Norio; Ko, Young Hyeh; Morishima, Yasuo; Ohshima, Koichi; Nakamura, Shigeo; Seto, Masao.

In: Blood, Vol. 118, No. 12, 22.09.2011, p. 3195-3204.

Research output: Contribution to journalArticle

Karube, K, Nakagawa, M, Tsuzuki, S, Takeuchi, I, Honma, K, Nakashima, Y, Shimizu, N, Ko, YH, Morishima, Y, Ohshima, K, Nakamura, S & Seto, M 2011, 'Identification of FOXO3 and PRDM1 as tumor-suppressor gene candidates in NK-cell neoplasms by genomic and functional analyses', Blood, vol. 118, no. 12, pp. 3195-3204. https://doi.org/10.1182/blood-2011-04-346890
Karube, Kennosuke ; Nakagawa, Masao ; Tsuzuki, Shinobu ; Takeuchi, Ichiro ; Honma, Keiichiro ; Nakashima, Yasuhiro ; Shimizu, Norio ; Ko, Young Hyeh ; Morishima, Yasuo ; Ohshima, Koichi ; Nakamura, Shigeo ; Seto, Masao. / Identification of FOXO3 and PRDM1 as tumor-suppressor gene candidates in NK-cell neoplasms by genomic and functional analyses. In: Blood. 2011 ; Vol. 118, No. 12. pp. 3195-3204.
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AU - Takeuchi, Ichiro

AU - Honma, Keiichiro

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AU - Ko, Young Hyeh

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