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

被引:155
作者
Iqbal, J. [1 ]
Kucuk, C. [1 ]
deLeeuw, R. J. [2 ]
Srivastava, G. [3 ,4 ]
Tam, W. [5 ]
Geng, H. [6 ]
Klinkebiel, D. [7 ]
Christman, J. K. [7 ]
Patel, K. [1 ]
Cao, K. [6 ]
Shen, L. [3 ,4 ]
Dybkaer, K. [8 ]
Tsui, I. F. L. [2 ]
Ali, H. [6 ]
Shimizu, N. [9 ]
Au, W. Y. [3 ,4 ]
Lam, W. L. [2 ]
Chan, W. C. [1 ]
机构
[1] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE 68198 USA
[2] British Columbia Canc Res Ctr, Vancouver, BC V5Z 1L3, Canada
[3] Univ Hong Kong, Dept Pathol, Hong Kong, Hong Kong, Peoples R China
[4] Univ Hong Kong, Dept Med, Hong Kong, Hong Kong, Peoples R China
[5] Cornell Univ, Weill Med Coll, Dept Pathol, New York, NY 10021 USA
[6] Univ Nebraska, Dept Comp Sci, Omaha, NE 68182 USA
[7] Univ Nebraska Med Ctr, Dept Biochem & Mol Biol, Omaha, NE 68198 USA
[8] Aarhus Univ Hosp, Aalborg Hosp, Dept Hematol, Aalborg, Denmark
[9] Tokyo Med & Dent Univ, Med Res Inst, Tokyo, Japan
关键词
NK-cell lymphoma; gene expression profiles; Array CGH; PRDM1; ATG5; CONSISTENT PATTERNS; BINDING; DNA; LYMPHOMA/LEUKEMIA; HYBRIDIZATION; EXPRESSION; AUTOPHAGY; LYMPHOMA; COREPRESSOR; METHYLATION;
D O I
10.1038/leu.2009.3
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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. Leukemia (2009) 23, 1139-1151; doi: 10.1038/leu.2009.3; published online 5 February 2009
引用
收藏
页码:1139 / 1151
页数:13
相关论文
共 49 条
[1]   Exchange of N-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-κB and β-amyloid precursor protein [J].
Baek, SH ;
Ohgi, KA ;
Rose, DW ;
Koo, EH ;
Glass, CK ;
Rosenfeld, MG .
CELL, 2002, 110 (01) :55-67
[2]  
Chan J K, 1998, Anat Pathol, V3, P77
[3]   AIM2 suppresses human breast cancer cell proliferation in vitro and mammary tumor growth in a mouse model [J].
Chen, IF ;
Fu, OY ;
Hung, JY ;
Liu, JC ;
Wang, HY ;
Wang, SC ;
Hou, MF ;
Hortobagyi, GN ;
Hung, MC .
MOLECULAR CANCER THERAPEUTICS, 2006, 5 (01) :1-7
[4]   Comprehensive whole genome array CGH profiling of mantle cell lymphoma model genomes [J].
de Leeuw, RJ ;
Davies, JJ ;
Rosenwald, A ;
Bebb, G ;
Gascoyne, RD ;
Dyer, MJS ;
Staudt, LM ;
Martinez-Climent, JA ;
Lam, WL .
HUMAN MOLECULAR GENETICS, 2004, 13 (17) :1827-1837
[5]   Genome wide transcriptional analysis of resting and IL2 activated human natural killer cells: gene expression signatures indicative of novel molecular signaling pathways [J].
Dybkaer, Karen ;
Iqbal, Javeed ;
Zhou, Guimei ;
Geng, Huimin ;
Xiao, Li ;
Schmitz, Alexander ;
d'Amore, Francesco ;
Chan, Wing C. .
BMC GENOMICS, 2007, 8 (1)
[6]   Specific chromosomal aberrations and amplification of the AIB1 nuclear receptor coactivator gene in pancreatic carcinomas [J].
Ghadimi, BM ;
Schröck, E ;
Walker, RL ;
Wangsa, D ;
Jauho, A ;
Meltzer, PS ;
Ried, T .
AMERICAN JOURNAL OF PATHOLOGY, 1999, 154 (02) :525-536
[7]   CYTOSINE METHYLATION DOES NOT AFFECT BINDING OF TRANSCRIPTION FACTOR-SP1 [J].
HARRINGTON, MA ;
JONES, PA ;
IMAGAWA, M ;
KARIN, M .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1988, 85 (07) :2066-2070
[8]  
Harris NL., 2001, Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues
[9]   Autophagy in cancer: Good, bad, or both? [J].
Hippert, Melanie M. ;
O'Toole, Patrick S. ;
Thorburn, Andrew .
CANCER RESEARCH, 2006, 66 (19) :9349-9351
[10]   SP1 TRANSCRIPTION FACTOR BINDS DNA AND ACTIVATES TRANSCRIPTION EVEN WHEN THE BINDING-SITE IS CPG METHYLATED [J].
HOLLER, M ;
WESTIN, G ;
JIRICNY, J ;
SCHAFFNER, W .
GENES & DEVELOPMENT, 1988, 2 (09) :1127-1135