The transactivating isoforms of p63 are overexpressed in high-grade follicular lymphomas independent of the occurrence of p63 gene amplification.
p63 is a p53-related gene mapping to 3q28 that codes for multiple mRNA transcripts with (TA-p63) or without (DeltaN-p63) transactivating effects on genes that promote cell differentiation and apoptosis. We analysed p63 alterations by immunohistochemistry, quantitative real-time RT-PCR and FISH in a series of 45 follicular lymphomas (FL). None of the tumours showed immunoreactivity for the p40 antibody, which recognizes only the truncated isoforms of p63, or DeltaN-p63 mRNA expression. Immunoreactivity for the 4A4 antibody, which recognizes both the transactivating and the truncated p63 isoforms, was found in 5 +/- 5.5%, 6.85 +/- 4.88% and 33.2 +/- 22.31% of grade I, II and III FL cells, respectively (p < 0.0001). Quantitative RT-PCR analysis showed that all cases but one had TA-p63 mRNA levels higher than non-neoplastic lymphocytes, and that TA-p63 mRNA expression correlated significantly (r = 0.9194, p < 0.0001) with the prevalence of p63 immunoreactivity. FISH extra signals for the p63 gene were found in seven (23.3%) of the 30 cases analysed (0/6 grade I, 2/15 grade II and 5/9 grade III; p = 0.01937). Further hybridizations showed a pattern highly suggestive of chromosome 3 polysomy in six cases. One of these cases also bore extra copies of the p63 and bcl-6 genes. Co-localization of p63 and IgH signals was found in one case. No association between the prevalence of p63 immunoreactivity and extra p63 gene signals was detectable when the cases were dichotomized according to a p63 immunoreactivity threshold of 10%. Our data suggest that TA-p63 is overexpressed in high-grade FL, possibly independent of the occurrence of gene abnormalities, and that it may be involved in the highly complex mechanism of regulation of apoptosis of FL cells.
Pruneri
Giancarlo
G
Division of Pathology and Laboratory Medicine, European Institute of Oncology, Milan, Italy. giancarlo.pruneri@ieo.it
Fabris
Sonia
S
Dell'Orto
Patrizia
P
Biasi
Maria Olivia
MO
Valentini
Stefano
S
Del Curto
Barbara
B
Laszlo
Daniele
D
Cattaneo
Laura
L
Fasani
Roberta
R
Rossini
Laura
L
Manzotti
Michela
M
Bertolini
Francesco
F
Martinelli
Giovanni
G
Neri
Antonino
A
Viale
Giuseppe
G
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D016147:Genes, Tumor Suppressor / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D008224:Lymphoma, Follicular / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins