Nucleotide sequence of a t(14;18) chromosomal breakpoint in follicular lymphoma and demonstration of a breakpoint-cluster region near a transcriptionally active locus on chromosome 18.

Abstract

The t(14;18)(q32;21) chromosomal translocation characteristic of follicular lymphomas is the most common cytogenetic abnormality known to be associated with any specific type of hematolymphoid malignancy. A fragment of DNA containing the crossover point between chromosomes 14 and 18 was cloned from the tumor cells of a patient with a follicular lymphoma carrying this translocation. Nucleotide sequence analysis of the breakpoint DNA revealed that the break in chromosome 14 occurred in joining region 4 (4) of the nonfunctional immunoglobulin heavy chain allele. This finding and other structural similarities of the breakpoint with the functional diversity region-joining region (D-J) joint in this lymphoma suggest that D-J recombination enzymes played a role in the mechanism of the t(14;18) translocation. Hybridization analysis of DNA from 40 follicular lymphomas showed that the majority of t(14;18) translocations occur on chromosome 18 DNA within 4.2 kilobases of the cloned breakpoint. A DNA probe from this breakpoint-cluster region detects transcription products in the tumor cells from which it was cloned and in a B-lymphoma cell line containing a t(14;18) translocation.

t(14;18), a journey to eternity

“…The chromosomal breakpoints on chromosome 18 are clustered in two regions: a 150 bp region in the 3′ untranslated region of bcl-2 which is called the major breakpoint region (MBR) and a 500 bp region 20 kilobases downstream of bcl-2 which is called the minor cluster region (MCR). [4][5][6] In t(14;18) positive follicular NHLs, about 79% of the breakpoints on chromosome 18 occur within the MBR and about 21% occur in the MCR (Table 1A).…”

“…It is now generally believed that the t(14;18) most likely results from a mistake during the IgH rearrangement process in the pre-B cell stage. 5,18 In agreement with this, occasional t(14;18)s have been described which are the result of erroneous IgH rearrangements during either the D H to D H Refs molecular USA 4/9 -----130 USA 29/48 -----131, 132 USA 14/20 -----133 World 37/64 -----134 USA -9/18 2/18 12/18 a --5 6 USA -21/36 11/36 32/36 --135 USA -11/17 ----136 USA 10/13 21/31 ----137 USA -11/37 ---- …”

Essential role of active nuclear transport in apoptosis

“…The protooncogene bcl-2 (Bakhshi et al 1985;Cleary & Sklar 1985;Tsujimoto et al 1985) and its relative bcl-x (Boise et al 1993), whose C. elegans homologue is ced-9 (Hengartner & Horvitz 1994), can inhibit the apoptosis induced by a variety of stimuli (Vaux et al 1988;Tsujimoto 1989;Nunez et al 1990), indicating that the Bcl-2 family negatively regulates a key event in a common pathway of apoptosis. As shown in the summary figure, the target of the Bcl-2 function appears to act upstream of the ICE protease cascade (Chinnaiyan et al 1996;Shimizu et al 1996a), presumably through regulating the levels of mitochondrial membrane potential in a variety of cell death systems (Shimizu et al 1996b;Zamzami et al 1996).…”

True

“…1,2 Bcl-2 contributes to the expansion of (pre) neoplastic cells, by promoting cell survival rather than by stimulating proliferation. 3,4 In fact, recent studies indicate that Bcl-2 can inhibit proliferation by retardation of the cell cycle entry, [5][6][7][8][9] which is in line with clinical observations that high Bcl-2 associates with slowly progressing disease and a low percentage of Sphase cells in some malignancies, notably lymphoma.…”

“…To this end, we have tested whether correlations exist between expression levels of Bcl-2 family members and clinical or cell biological features at presentation. In addition, we have investigated whether there was a correlation between the pretreatment expression levels of the Bcl-2 family and drug response at three levels; (1) in vitro drug resistance for prednisolone (PRD), vincristine (VCR) and l-asparaginase (ASP) and its combination; (2) in vivo response at day 8 after 1 week monotherapy with prednisone; and (3) long-term clinical outcome.…”