In vivo p53 response and immune reaction underlie highly effective low-dose radiotherapy in follicular lymphoma.
Very low-dose irradiation (2 x 2 Gy) is a new, effective, and safe local treatment for follicular lymphoma. To understand the biologic mechanisms of this extremely effective response, we compared by microarray the gene-expression profile of patients' biopsies taken before and after radiation. In all patients, a major and consistent induction of p53 target genes was seen. p53 targets involved in cell-cycle arrest and apoptosis showed the same mode of regulation, indicating that, in vivo, both are activated simultaneously. p53 up-regulation and p53-mediated proliferation arrest and apoptosis were substantiated using immunohistochemistry, with activation of both the intrinsic and the extrinsic apoptotic pathways. The other induced genes revealed a whole set of biologically meaningful genes related to macrophage activation and TH1 immune response. Immunohistochemical analysis suggested a specific activation or differentiation of resident macrophages by apoptotic cells. These biologic insights are important arguments to advocate the use of low-dose radiotherapy as an effective palliative treatment for follicular lymphoma. Moreover, this study is the first in vivo report of the radiation-induced p53 apoptotic response in patients and suggests that this apoptotic response is not immunologically silent.
Knoops
Laurent
L
Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Haas
Rick
R
de Kemp
Sanne
S
Majoor
Donné
D
Broeks
Annegien
A
Eldering
Eric
E
de Boer
Jan Paul
JP
Verheij
Marcel
M
van Ostrom
Conny
C
de Vries
Annemieke
A
van't Veer
Laura
L
de Jong
Daphne
D
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000528:radiation effects; D005260:Female; D005720:Gamma Rays; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D007124:Immunoenzyme Techniques; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology / Q000532:radiotherapy; D008224:Lymphoma, Follicular / Q000276:immunology* / Q000532:radiotherapy*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000276:immunology / Q000532:radiotherapy; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53