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Article: Genomic analyses reveal global functional alterations that promote tumor growth and novel tumor suppressor genes in natural killer-cell malignancies
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TitleGenomic analyses reveal global functional alterations that promote tumor growth and novel tumor suppressor genes in natural killer-cell malignancies
 
AuthorsIqbal, J3
Kucuk, C3
deLeeuw, RJ5
Srivastava, G2
Tam, W1
Geng, H6
Klinkebiel, D3
Christman, JK3
Patel, K3
Cao, K6
Shen, L2
Dybkaer, K4
Tsui, IFL5
Ali, H6
Shimizu, N7
Au, WY2
Lam, WL5
Chan, WC3
 
Issue Date2009
 
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/leu
 
CitationLeukemia, 2009, v. 23 n. 6, p. 1139-1151 [How to Cite?]
DOI: http://dx.doi.org/10.1038/leu.2009.3
 
AbstractNatural killer (NK)-cell malignancies are among the most aggressive lymphoid neoplasms with very poor prognosis. We performed array comparative genomic hybridization analysis on a number of NK cell lines and primary tumors to gain better understanding of the pathogenesis and tumor biology of these malignancies. We also obtained transcriptional profiles of genes residing in these regions and compared them with normal and activated NK cells. Only 30-50% of the genes residing in the gained or deleted regions showed corresponding increased or decreased expression. However, many of the upregulated genes in regions of gain are functionally important for the proliferation and growth of the neoplastic population. Genes downregulated in regions of loss included many transcription factors or repressors, tumor suppressors or negative regulators of the cell cycle. The minimal common region of deletion in 6q21 included three known genes (PRDM1, ATG5 and AIM1) showing generally low expression. Mutations resulting in truncated PRDM1 and changes in conserved amino-acid sequences of AIM1 were detected. Highly methylated CpG islands 5′ of PRDM1 and AIM1 correlated with low expression of the transcripts. Reversal of methylation by Decitabine induced expression of PRDM1 and cell death. In conclusion, we have shown a general tumor-promoting effect of genetic alterations and have identified PRDM1 as the most likely target gene in del6q21. ATG5, an essential gene for autophagy and AIM1, a gene implicated in melanoma, may also participate in the functional abnormalities.
 
ISSN0887-6924
2013 Impact Factor: 9.379
2013 SCImago Journal Rankings: 4.500
 
DOIhttp://dx.doi.org/10.1038/leu.2009.3
 
ISI Accession Number IDWOS:000266820700015
Funding AgencyGrant Number
NCI Grant5U01/CA114778
Genome center Canada/British Columbia
NIHP20 RR016469
INBRE Program of the National Center for Research Resources
Funding Information:

This study was supported in part by a NCI Grant (5U01/CA114778) and funds from Genome center Canada/British Columbia. We thank Dr Junjiro Tsuchiyama and Dr Yoshitoyo Kagami for NK-YS and HANK-1 cell lines, respectively. The UNMC Microarray Core Facility Dr James Eudy supported partially by NIH Grant P20 RR016469 from the INBRE Program of the National Center for Research Resources.

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorIqbal, J
 
dc.contributor.authorKucuk, C
 
dc.contributor.authordeLeeuw, RJ
 
dc.contributor.authorSrivastava, G
 
dc.contributor.authorTam, W
 
dc.contributor.authorGeng, H
 
dc.contributor.authorKlinkebiel, D
 
dc.contributor.authorChristman, JK
 
dc.contributor.authorPatel, K
 
dc.contributor.authorCao, K
 
dc.contributor.authorShen, L
 
dc.contributor.authorDybkaer, K
 
dc.contributor.authorTsui, IFL
 
dc.contributor.authorAli, H
 
dc.contributor.authorShimizu, N
 
dc.contributor.authorAu, WY
 
dc.contributor.authorLam, WL
 
dc.contributor.authorChan, WC
 
dc.date.accessioned2010-05-31T03:47:45Z
 
dc.date.available2010-05-31T03:47:45Z
 
dc.date.issued2009
 
dc.description.abstractNatural killer (NK)-cell malignancies are among the most aggressive lymphoid neoplasms with very poor prognosis. We performed array comparative genomic hybridization analysis on a number of NK cell lines and primary tumors to gain better understanding of the pathogenesis and tumor biology of these malignancies. We also obtained transcriptional profiles of genes residing in these regions and compared them with normal and activated NK cells. Only 30-50% of the genes residing in the gained or deleted regions showed corresponding increased or decreased expression. However, many of the upregulated genes in regions of gain are functionally important for the proliferation and growth of the neoplastic population. Genes downregulated in regions of loss included many transcription factors or repressors, tumor suppressors or negative regulators of the cell cycle. The minimal common region of deletion in 6q21 included three known genes (PRDM1, ATG5 and AIM1) showing generally low expression. Mutations resulting in truncated PRDM1 and changes in conserved amino-acid sequences of AIM1 were detected. Highly methylated CpG islands 5′ of PRDM1 and AIM1 correlated with low expression of the transcripts. Reversal of methylation by Decitabine induced expression of PRDM1 and cell death. In conclusion, we have shown a general tumor-promoting effect of genetic alterations and have identified PRDM1 as the most likely target gene in del6q21. ATG5, an essential gene for autophagy and AIM1, a gene implicated in melanoma, may also participate in the functional abnormalities.
 
dc.description.naturelink_to_subscribed_fulltext
 
dc.identifier.citationLeukemia, 2009, v. 23 n. 6, p. 1139-1151 [How to Cite?]
DOI: http://dx.doi.org/10.1038/leu.2009.3
 
dc.identifier.citeulike4012831
 
dc.identifier.doihttp://dx.doi.org/10.1038/leu.2009.3
 
dc.identifier.epage1151
 
dc.identifier.hkuros154462
 
dc.identifier.isiWOS:000266820700015
Funding AgencyGrant Number
NCI Grant5U01/CA114778
Genome center Canada/British Columbia
NIHP20 RR016469
INBRE Program of the National Center for Research Resources
Funding Information:

This study was supported in part by a NCI Grant (5U01/CA114778) and funds from Genome center Canada/British Columbia. We thank Dr Junjiro Tsuchiyama and Dr Yoshitoyo Kagami for NK-YS and HANK-1 cell lines, respectively. The UNMC Microarray Core Facility Dr James Eudy supported partially by NIH Grant P20 RR016469 from the INBRE Program of the National Center for Research Resources.

 
dc.identifier.issn0887-6924
2013 Impact Factor: 9.379
2013 SCImago Journal Rankings: 4.500
 
dc.identifier.issue6
 
dc.identifier.openurl
 
dc.identifier.pmid19194464
 
dc.identifier.scopuseid_2-s2.0-67349138549
 
dc.identifier.spage1139
 
dc.identifier.urihttp://hdl.handle.net/10722/59325
 
dc.identifier.volume23
 
dc.languageeng
 
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/leu
 
dc.publisher.placeUnited Kingdom
 
dc.relation.ispartofLeukemia
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshAdult
 
dc.subject.meshAged
 
dc.subject.meshCell Proliferation
 
dc.subject.meshChromosomes, Human, Pair 6
 
dc.subject.meshComparative Genomic Hybridization
 
dc.subject.meshCrystallins - genetics
 
dc.subject.meshGene Expression Profiling
 
dc.subject.meshGene Expression Regulation, Neoplastic
 
dc.subject.meshGenes, Tumor Suppressor
 
dc.subject.meshHumans
 
dc.subject.meshKiller Cells, Natural - pathology
 
dc.subject.meshLymphoma - genetics - pathology
 
dc.subject.meshMembrane Proteins - genetics
 
dc.subject.meshMicrotubule-Associated Proteins - genetics
 
dc.subject.meshMiddle Aged
 
dc.subject.meshRepressor Proteins - genetics
 
dc.subject.meshTumor Cells, Cultured
 
dc.titleGenomic analyses reveal global functional alterations that promote tumor growth and novel tumor suppressor genes in natural killer-cell malignancies
 
dc.typeArticle
 
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Author Affiliations
  1. Weill Cornell Medical College
  2. The University of Hong Kong
  3. University of Nebraska Medical Center
  4. Aalborg Sygehus
  5. BC Cancer Research Centre
  6. University of Nebraska at Omaha
  7. Tokyo Medical and Dental University