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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

TitleGenomic analyses reveal global functional alterations that promote tumor growth and novel tumor suppressor genes in natural killer-cell malignancies
Authors
Issue Date2009
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/leu
Citation
Leukemia, 2009, v. 23 n. 6, p. 1139-1151 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/59325
ISSN
2014 Impact Factor: 10.431
2013 SCImago Journal Rankings: 4.500
ISI Accession Number ID
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.

References

 

DC FieldValueLanguage
dc.contributor.authorIqbal, Jen_HK
dc.contributor.authorKucuk, Cen_HK
dc.contributor.authordeLeeuw, RJen_HK
dc.contributor.authorSrivastava, Gen_HK
dc.contributor.authorTam, Wen_HK
dc.contributor.authorGeng, Hen_HK
dc.contributor.authorKlinkebiel, Den_HK
dc.contributor.authorChristman, JKen_HK
dc.contributor.authorPatel, Ken_HK
dc.contributor.authorCao, Ken_HK
dc.contributor.authorShen, Len_HK
dc.contributor.authorDybkaer, Ken_HK
dc.contributor.authorTsui, IFLen_HK
dc.contributor.authorAli, Hen_HK
dc.contributor.authorShimizu, Nen_HK
dc.contributor.authorAu, WYen_HK
dc.contributor.authorLam, WLen_HK
dc.contributor.authorChan, WCen_HK
dc.date.accessioned2010-05-31T03:47:45Z-
dc.date.available2010-05-31T03:47:45Z-
dc.date.issued2009en_HK
dc.identifier.citationLeukemia, 2009, v. 23 n. 6, p. 1139-1151en_HK
dc.identifier.issn0887-6924en_HK
dc.identifier.urihttp://hdl.handle.net/10722/59325-
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.en_HK
dc.languageengen_HK
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/leuen_HK
dc.relation.ispartofLeukemiaen_HK
dc.subject.meshAdulten_HK
dc.subject.meshAgeden_HK
dc.subject.meshCell Proliferationen_HK
dc.subject.meshChromosomes, Human, Pair 6en_HK
dc.subject.meshComparative Genomic Hybridizationen_HK
dc.subject.meshCrystallins - geneticsen_HK
dc.subject.meshGene Expression Profilingen_HK
dc.subject.meshGene Expression Regulation, Neoplasticen_HK
dc.subject.meshGenes, Tumor Suppressoren_HK
dc.subject.meshHumansen_HK
dc.subject.meshKiller Cells, Natural - pathologyen_HK
dc.subject.meshLymphoma - genetics - pathologyen_HK
dc.subject.meshMembrane Proteins - geneticsen_HK
dc.subject.meshMicrotubule-Associated Proteins - geneticsen_HK
dc.subject.meshMiddle Ageden_HK
dc.subject.meshRepressor Proteins - geneticsen_HK
dc.subject.meshTumor Cells, Cultureden_HK
dc.titleGenomic analyses reveal global functional alterations that promote tumor growth and novel tumor suppressor genes in natural killer-cell malignanciesen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0887-6924&volume=&spage=Epub 2009 Feb 5&epage=&date=2009&atitle=Genomic+analyses+reveal+global+functional+alterations+that+promote+tumor+growth+and+novel+tumor+suppressor+genes+in+natural+killer-cell+malignanciesen_HK
dc.identifier.emailSrivastava, G:gopesh@pathology.hku.hken_HK
dc.identifier.authoritySrivastava, G=rp00365en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1038/leu.2009.3en_HK
dc.identifier.pmid19194464en_HK
dc.identifier.scopuseid_2-s2.0-67349138549en_HK
dc.identifier.hkuros154462en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-67349138549&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume23en_HK
dc.identifier.issue6en_HK
dc.identifier.spage1139en_HK
dc.identifier.epage1151en_HK
dc.identifier.isiWOS:000266820700015-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.citeulike4012831-

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