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 language | English |
|---|---|
| Pages (from-to) | 3195-3204 |
| Number of pages | 10 |
| Journal | Blood |
| Volume | 118 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - Sep 22 2011 |
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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 journal › Article
}
TY - JOUR
T1 - Identification of FOXO3 and PRDM1 as tumor-suppressor gene candidates in NK-cell neoplasms by genomic and functional analyses
AU - Karube, Kennosuke
AU - Nakagawa, Masao
AU - Tsuzuki, Shinobu
AU - Takeuchi, Ichiro
AU - Honma, Keiichiro
AU - Nakashima, Yasuhiro
AU - Shimizu, Norio
AU - Ko, Young Hyeh
AU - Morishima, Yasuo
AU - Ohshima, Koichi
AU - Nakamura, Shigeo
AU - Seto, Masao
PY - 2011/9/22
Y1 - 2011/9/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=80053121023&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80053121023&partnerID=8YFLogxK
U2 - 10.1182/blood-2011-04-346890
DO - 10.1182/blood-2011-04-346890
M3 - Article
C2 - 21690554
AN - SCOPUS:80053121023
VL - 118
SP - 3195
EP - 3204
JO - Blood
JF - Blood
SN - 0006-4971
IS - 12
ER -