Genetic alterations of the retinoblastoma-related gene RB2/p130 identify different pathogenetic mechanisms in and among Burkitt's lymphoma subtypes.
Alterations of cell cycle-associated genes probably contribute to the pathogenesis of Burkitt's Lymphoma (BL), in addition to c-myc translocation. Mutations disrupting the nuclear localization signal of the retinoblastoma-related gene RB2/p130 have been documented recently in BL cell lines and primary tumors. Given the importance of the RB2/p130 gene in controlling cell growth, mutations of this gene may result in uncontrolled cell proliferation. We tested the expression and genomic organization of the RB2/p130 gene in relation to the proliferative features of a series of BL samples collected from the endemic and sporadic regions, regardless of whether the samples were acquired immune deficiency syndrome (AIDS)-related. The expression of the Rb2/p130, p107, and cell proliferation-related proteins (cyclin A and B) was determined by immunohistochemistry. The structures of exons 19 through 22 of the RB2/p130 gene, encoding for the B domain and C terminus, were analyzed by polymerase chain reaction (PCR) analysis and single-strand conformation polymorphism (SSCP) technique. The direct PCR products were sequenced to identify the actual mutations. Our results suggest that BL is composed of a mixture of molecular types with distinct genetic and phenotypic patterns, probably resulting from different pathogenetic mechanisms. In endemic BL, the RB2/p130 gene is mutated in most of the cases, and the protein is restricted to the cytoplasm. In AIDS-related BL, high levels of nuclear expression of the wild-type pRb2/p130, p107, and cell proliferation-related proteins were detected. This finding is in line with the molecular mechanisms observed in virus-linked oncogenesis. Sporadic BLs were mainly characterized by the low nuclear values of the wild-type pRb2/p130 and, conversely, the high values of p107. The increased cell proliferation due to different alterations of cell growth control by Rb-related proteins may be the first step in lymphomagenesis, during which additional genetic changes, including missense mutations of c-myc, may subsequently occur.
Cinti
C
C
Institute of Normal and Pathologic Cytomorphology, Consiglio Nazionale delle Ricerche, Bologna, Italy.
Leoncini
L
L
Nyongo
A
A
Ferrari
F
F
Lazzi
S
S
Bellan
C
C
Vatti
R
R
Zamparelli
A
A
Cevenini
G
G
Tosi
G M
GM
Claudio
P P
PP
Maraldi
N M
NM
Tosi
P
P
Giordano
A
A
D000293:Adolescent; D000328:Adult; D017209:Apoptosis; D002051:Burkitt Lymphoma / Q000145:classification / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D019925:Cyclin A / Q000235:genetics / Q000378:metabolism; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D004273:DNA, Neoplasm / Q000032:analysis; D004279:DNA, Viral / Q000032:analysis; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D017403:In Situ Hybridization; D016483:Lymphoma, AIDS-Related / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008940:Mitotic Index; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011506:Proteins; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130
D019925:Cyclin A; D019926:Cyclin B; D017931:DNA Primers; D004273:DNA, Neoplasm; D004279:DNA, Viral; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011506:Proteins; C493844:RBL1 protein, human; C493837:RBL2 protein, human; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130