Vav-1 expression correlates with NFκB activation and CD40-mediated cell death in diffuse large B-cell lymphoma cell lines.
Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy with a variable response to therapy. We have previously shown that DLBCL cell lines differ in their susceptibility to CD40-mediated cell death, and that resistance to CD40-targeted antibodies correlated with increased expression of markers of immature B-cell and absence of Vav-1 mRNA. We used gene expression profiling to investigate the mechanism of CD40 resistance in these cell lines, and found that resistance correlated with lack of Vav-1 and inability to activate NFκB upon CD40 ligation. Analysis of tissue microarrays of 213 DLBCL cases revealed that Vav-1 expression correlated with a higher proliferative index and the presence of the post-germinal centre marker Irf-4. Our results suggest that Vav-1 expression may be associated with activated B-cell DLBCL origin and higher proliferative activity, and indicate Vav-1 as a potential marker to identify tumours likely to respond to CD40-targeted therapies.
Hollmann
Annette
A
Montreal Center for Experimental Therapeutics in Cancer, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montréal, Quebec, Canada. sharkies10k@hotmail.com
Aloyz
Raquel
R
Baker
Kristi
K
Dirnhofer
Stephan
S
Owens
Trevor
T
Sladek
Robert
R
Tzankov
Alexandar
A
D000368:Aged; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D050835:Interferon Regulatory Factors / Q000096:biosynthesis / Q000378:metabolism; D019394:Ki-67 Antigen / Q000096:biosynthesis; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D011379:Prognosis; D051567:Proto-Oncogene Proteins c-vav / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D000099218:Interferon Regulatory Factor-4
D019013:CD40 Antigens; D050835:Interferon Regulatory Factors; D019394:Ki-67 Antigen; D016328:NF-kappa B; D051567:Proto-Oncogene Proteins c-vav; D012333:RNA, Messenger; D000099218:Interferon Regulatory Factor-4; C496618:VAV1 protein, human