Differential gene expression in anaplastic lymphoma kinase-positive and anaplastic lymphoma kinase-negative anaplastic large cell lymphomas.
Anaplastic large cell lymphoma (ALCL) is an aggressive large T- or null-cell lymphoma. Most ALCLs arising in children and young adults express a constitutively active receptor tyrosine kinase, anaplastic lymphoma kinase (ALK). Anaplastic large cell lymphomas lacking ALK are clinically heterogeneous and their pathogenesis is unknown. This study is the first complementary DNA (cDNA) microarray analysis using RNA extracted from tumor tissue (7 ALK+ ALCLs and 7 ALK- ALCLs) to identify genes differentially expressed or shared between the ALK+ and ALK- tumors. Unsupervised hierarchical clustering using the top 11 most statistically significant discriminator cDNAs correctly grouped all ALK+ and ALK- tumors. Hierarchical clustering analysis using the 44 cDNAs with the greatest differential expression between ALK+ and ALK- RNAs grouped 6 of 7 ALK+ ALCLs together and 1 ALK+ ALCL with the ALK- group. In general, ALK+ tumors overexpress genes encoding signal transduction molecules (SYK , LYN , CDC37) and underexpress transcription factor genes (including HOXC6 and HOX A3 ) compared with the ALK- group. Cyclin D3 was overexpressed in the ALK+ group and the cell cycle inhibitor p19INK4D was decreased in the ALK- group, suggesting different mechanisms of promoting G 1 /S transition. Both groups had similar proliferation rates. Genes highly expressed in both ALK- and ALK+ ALCLs included kinases (LCK, protein kinase C, vav2, and NKIAMRE) and antiapoptotic molecules, suggesting possible common pathogenetic mechanisms as well.
Thompson
Mary Ann
MA
Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37332, USA. mary.ann.thompson@vanderbilt.edu
Stumph
Jennifer
J
Henrickson
Sarah E
SE
Rosenwald
Andreas
A
Wang
Qifu
Q
Olson
Sandy
S
Brandt
Stephen J
SJ
Roberts
Jeremy
J
Zhang
Xueqiong
X
Shyr
Yu
Y
Kinney
Marsha C
MC
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002648:Child; D056743:Cyclin D3; D050764:Cyclin-Dependent Kinase Inhibitor p19; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D016403:Lymphoma, Large B-Cell, Diffuse / Q000201:enzymology* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases; D020133:Reverse Transcriptase Polymerase Chain Reaction
C534696:CCND3 protein, human; C493974:CDKN2D protein, human; D018797:Cell Cycle Proteins; D056743:Cyclin D3; D050764:Cyclin-Dependent Kinase Inhibitor p19; D016213:Cyclins; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases