Genomic analyses reveal global functional alterations that promote tumor growth and novel tumor suppressor genes in natural killer-cell malignancies

Javeed Iqbal, C. Kucuk, R. J. deLeeuw, G. Srivastava, W. Tam, H. Geng, David L Klinkebiel, J. K. Christman, K. Patel, K. Cao, L. Shen, K. Dybkaer, I. F L Tsui, Hesham H Ali, N. Shimizu, W. Y. Au, W. L. Lam, W. C. Chan

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Abstract

Natural 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.

Original languageEnglish (US)
Pages (from-to)1139-1151
Number of pages13
JournalLeukemia
Volume23
Issue number6
DOIs
StatePublished - Jan 1 2009

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Tumor Suppressor Genes
Natural Killer Cells
Growth
Genes
Neoplasms
decitabine
CpG Islands
Comparative Genomic Hybridization
Population Growth
Essential Genes
Autophagy
Methylation
Amino Acid Sequence
Melanoma
Cell Cycle
Cell Death
Transcription Factors
Down-Regulation
Cell Line
Mutation

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Genomic analyses reveal global functional alterations that promote tumor growth and novel tumor suppressor genes in natural killer-cell malignancies. / Iqbal, Javeed; Kucuk, C.; deLeeuw, R. J.; Srivastava, G.; Tam, W.; Geng, H.; Klinkebiel, David L; Christman, J. K.; Patel, K.; Cao, K.; Shen, L.; Dybkaer, K.; Tsui, I. F L; Ali, Hesham H; Shimizu, N.; Au, W. Y.; Lam, W. L.; Chan, W. C.

In: Leukemia, Vol. 23, No. 6, 01.01.2009, p. 1139-1151.

Research output: Contribution to journalArticle

Iqbal, J, Kucuk, C, deLeeuw, RJ, Srivastava, G, Tam, W, Geng, H, Klinkebiel, DL, Christman, JK, Patel, K, Cao, K, Shen, L, Dybkaer, K, Tsui, IFL, Ali, HH, Shimizu, N, Au, WY, Lam, WL & Chan, WC 2009, 'Genomic analyses reveal global functional alterations that promote tumor growth and novel tumor suppressor genes in natural killer-cell malignancies', Leukemia, vol. 23, no. 6, pp. 1139-1151. https://doi.org/10.1038/leu.2009.3
Iqbal, Javeed ; Kucuk, C. ; deLeeuw, R. J. ; Srivastava, G. ; Tam, W. ; Geng, H. ; Klinkebiel, David L ; Christman, J. K. ; Patel, K. ; Cao, K. ; Shen, L. ; Dybkaer, K. ; Tsui, I. F L ; Ali, Hesham H ; Shimizu, N. ; Au, W. Y. ; Lam, W. L. ; Chan, W. C. / Genomic analyses reveal global functional alterations that promote tumor growth and novel tumor suppressor genes in natural killer-cell malignancies. In: Leukemia. 2009 ; Vol. 23, No. 6. pp. 1139-1151.
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abstract = "Natural 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.",
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AU - Kucuk, C.

AU - deLeeuw, R. J.

AU - Srivastava, G.

AU - Tam, W.

AU - Geng, H.

AU - Klinkebiel, David L

AU - Christman, J. K.

AU - Patel, K.

AU - Cao, K.

AU - Shen, L.

AU - Dybkaer, K.

AU - Tsui, I. F L

AU - Ali, Hesham H

AU - Shimizu, N.

AU - Au, W. Y.

AU - Lam, W. L.

AU - Chan, W. C.

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N2 - Natural 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.

AB - Natural 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.

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