Involvement of multiple signaling pathways in follicular lymphoma transformation: p38-mitogen-activated protein kinase as a target for therapy
- Kojo S. J. Elenitoba-Johnson*,†,‡,
- Stephen D. Jenson*,
- Robert T. Abbott*,
- Robert A. Palais§,
- Sandra D. Bohling†,
- Zhaosheng Lin†,
- Sheryl Tripp†,
- Paul J. Shami¶,
- Lai Y. Wang¶,
- Robert W. Coupland∥,
- Rena Buckstein**,
- Bayardo Perez-Ordonez††,
- Sherrie L. Perkins*,†,
- Ian D. Dube††, and
- Megan S. Lim*,†,‡
- *Department of Pathology, †Associated Regional and University Pathologists Institute for Clinical and Experimental Pathology, §Department of Mathematics, and ¶Division of Medical Oncology, University of Utah, Salt Lake City, UT 84132; ∥Cross Cancer Institute, Edmonton, AB, Canada T6G 1Z2; and **Advanced Therapeutics Program and ††Department of Pathology, Sunnybrook and Women's College Health Sciences Centre, Toronto, ON, Canada M4N 3M5
-
Edited by Janet D. Rowley, University of Chicago Medical Center, Chicago, IL (received for review December 9, 2002)
Abstract
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 p38β-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.
Footnotes
-
↵ ‡ To whom correspondence should be addressed. E-mail: kojo.elenitobaj{at}path.utah.edu or megan.lim{at}path.utah.edu.
-
This paper was submitted directly (Track II) to the PNAS office.
-
Abbreviations: FL, follicular lymphoma; DLBCL, diffuse large B cell lymphoma; GCB, germinal center B cell; ABC, activated B cell; MAPK, mitogen-activated protein kinase; IHC, immunohistochemistry; qRT-PCR, quantitative RT-PCR; IgH, Ig heavy chain gene; PLA, phospholipase A; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling.
- Copyright © 2003, The National Academy of Sciences
