Morphologic transformation of follicular lymphoma is associated with somatic mutation of the translocated Bcl-2 gene.

Abstract:

:Follicular lymphoma (FL) is a low-grade B-cell non-Hodgkin's lymphoma (NHL) that frequently transforms into diffuse aggressive NHL. The majority of FLs display a t(14; 18) translocation that places the bcl-2 gene into juxtaposition with the lg heavy-chain (H) gene locus. Morphologically transformed malignant FL cells retain their t(14;18) translocation and may acquire additional genetic abnormalities. We analyzed serial biopsy specimens from eight patients with FL for secondary alterations of the rearranged bcl-2 gene in the breakpoint and open reading frame (ORF) regions. Two cases of FL showed no histologic alteration in the second biopsy, and six cases of FL showed morphologic transformation to diffuse large-cell lymphoma (DLL) in the second biopsy. Polymerase chain reaction (PCR) amplification, cloning, and sequencing of the junctional region of the hybrid bcl-2/IgH genes showed identical nucleotide sequences in multiple biopsy specimens of FL that did not show morphologic transformation. In patients in whom FL cells underwent morphologic transformation, FL and autologous DLL cells displayed identical bcl-2/IgH gene nucleotide sequences in five cases and different sequences in one case. In the case for which FL and DLL cells showed different bcl-2/IgH junctional sequences, DLL cells incorporated larger bcl-2 and Ig-joining (JH) gene fragments than the corresponding FL cells, suggesting that DLL clones developed by a distinct t(14; 18) translocation rather than by alteration of the hybrid bcl-2/IgH gene detected in the FL cells. In all eight cases, neither FL nor DLL cells showed alterations of bcl-2 gene sequences in the breakpoint region, suggesting high conservation of the bcl-2 gene during both t(14; 18) translocation and morphologic transformation of the FL cells. PCR single-strand conformation polymorphism (SSCP) and sequence analyses were performed for identification of structural alterations of the bcl-2 gene in the ORF region corresponding to the 239-amino acid p26-bcl-2 alpha protein. A total of 11 point mutations of the ORF were detected in DLL cells of three transformed NHLs, but no alteration of the ORF was detected in FL cells. Four of 11 mutations, at positions 29, 46, 59, and 106, yielded amino acid replacements. These findings demonstrate that FL and DLL cells may be clonally related or unrelated. They also show that transformation of FL cells may be associated with somatic point mutations of the bcl-2 proto-oncogene ORF sequence resulting in alteration of the p26-bcl-2 alpha gene product.

journal_name

Blood

journal_title

Blood

authors

Matolcsy A,Casali P,Warnke RA,Knowles DM

subject

Has Abstract

pub_date

1996-11-15 00:00:00

pages

3937-44

issue

10

eissn

0006-4971

issn

1528-0020

journal_volume

88

pub_type

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