Involvement of multiple signaling pathways in follicular lymphoma transformation: p38-mitogen-activated protein kinase as a target for therapy.
Follicular lymphoma (FL) is the most common form of low-grade non-Hodgkin's lymphoma. Transformation to diffuse large B cell lymphoma (DLBCL) is an important cause of mortality. Using cDNA microarray analysis we identified 113 transformation-associated genes whose expression differed consistently between serial clonally related samples of FL and DLBCL occurring within the same individual. Quantitative RT-PCR validated the microarray results and assigned blinded independent group of 20 FLs, 20 DLBCLs, and five transformed lymphoma-derived cell lines with 100%, 70%, and 100% accuracy, respectively. Notably, growth factor cytokine receptors and p38beta-mitogen-activated protein kinase (MAPK) were differentially expressed in the DLBCLs. Immunohistochemistry of another blinded set of samples demonstrated expression of phosphorylated p38MAPK in 6/6 DLBCLs and 1/5 FLs, but not in benign germinal centers. SB203580 an inhibitor of p38MAPK specifically induced caspase-3-mediated apoptosis in t(14;18)+/p38MAPK+-transformed FL-derived cell lines. Lymphoma growth was also inhibited in SB203580-treated NOD-SCID mice. Our results implicate p38MAPK dysregulation in FL transformation and suggest that molecular targeting of specific elements within this pathway should be explored for transformed FL therapy.
Elenitoba-Johnson
Kojo S J
KS
Department of Pathology, Associated Regional and University Pathologists Institute for Clinical and Experimental Pathology, University of Utah, Salt Lake City, UT 84132, USA. kojo.elenitobaj@path.utah.edu
Jenson
Stephen D
SD
Abbott
Robert T
RT
Palais
Robert A
RA
Bohling
Sandra D
SD
Lin
Zhaosheng
Z
Tripp
Sheryl
S
Shami
Paul J
PJ
Wang
Lai Y
LY
Coupland
Robert W
RW
Buckstein
Rena
R
Perez-Ordonez
Bayardo
B
Perkins
Sherrie L
SL
Dube
Ian D
ID
Lim
Megan S
MS
D017209:Apoptosis / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020869:Gene Expression Profiling; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D008224:Lymphoma, Follicular / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011725:Pyridines / Q000494:pharmacology; D018121:Receptors, Cytokine / Q000235:genetics; D017978:Receptors, Growth Factor / Q000235:genetics; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D018121:Receptors, Cytokine; D017978:Receptors, Growth Factor; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580