BCL-6 in diffuse large-cell lymphomas.
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B-Lymphocytes↗
Biomedical subjects
S Chaganti
Publications and source records attributed to S Chaganti.
Chromosomal translocations cause deregulated BCL6 expression by promoter substitution in B cell lymphoma.
The BCL6 gene codes for a zinc-finger transcription factor and is involved in chromosomal rearrangements in 30-40% of diffuse large-cell lymphoma (DLCL). These rearrangements cluster within the 5' regulatory region of BCL6 spanning its first non-coding exon. To determine the functional consequences of these alterations, we have analyzed the structure of the rearranged BCL6 alleles and their corresponding RNA and protein species in two DLCL biopsies and one tumor cell line which carried the t(3;14)(q27;q32) translocation involving the BCL6 and immunoglobulin heavy-chain (IgH) loci. In all three cases, the breakpoints were mapped within the IgH switch region and the BCL6 first intron, leading to the juxtaposition of part of the IgH locus upstream and in the same transcriptional orientation to the BCL6 coding exons. An analysis of cDNA clones showed that these recombinations generate chimeric IgH-BCL6 transcripts which initiated from IgH germline transcript promoters (I mu or I gamma 3), but retain a normal BCL6 coding domain. In the tumor cell line, the chimeric I gamma 3-BCL6 allele, but not the germline BCL6 gene, was transcriptionally active and produced a normal BCL6 protein. These findings indicate that t(3;14) translocations alter BCL6 expression by promoter substitution and imply that the consequence of these alterations is the deregulated expression of a normal BCL6 protein.
Alleles↗
BCL-6 and the molecular pathogenesis of B-cell lymphoma.
The results presented identify the first genetic lesion associated with DLCL, the most clinically relevant form of NHL. Although no proof yet exists of a role for these lesions in DLCL pathogenesis, the feature of the BCL-6 gene product, its specific pattern of expression in B cells, and the clustering of lesions disrupting its regulatory domain strongly suggest that deregulation of BCL-6 expression may contribute to DLCL development. A more precise definition of the role of BCL-6 in normal and neoplastic B-cell development is the goal of ongoing study of transgenic mice engineered either to express BCL-6 under heterologous promoters or lacking BCL-6 function due to targeted deletions. In addition to contributing to the understanding of DLCL pathogenesis, the identification of BCL-6 lesions may have relevant clinical implications. DLCL represent a heterogeneous group of neoplasms which are treated homogeneously despite the fact that only 50% of patients experience long-term disease-free survival (Schneider et al. 1990). The fact that BCL-6 rearrangements identify biologically and clinically distinct subsets of DLCL suggests that these lesions may be useful as markers in selection of differential therapeutic strategies based on different risk groups. Furthermore, the BCL-6 rearrangements can be used to identify and monitor the malignant clone with sensitive PCR-based techniques. Since clinical remission has been observed in a significant fraction of DLCL cases, these markers may serve as critical tools for sensitive monitoring of minimal residual disease and early diagnosis of relapse (Gribben et al. 1993).
Animals↗
Diurnal variation in peak expiratory flow in healthy young adults.
Diurnal variability in peak expiratory flow (PEF) was studied for three days in 152 healthy volunteers aged 20-40 years, and expressed as amplitude percent mean (A%M) and standard deviation percent mean (SD%M). The commonest pattern (74.6%) observed was that of a nadir at waking in morning, a progressive rise upto late afternoon and a plateau or a small decrease at bedtime. Mean diurnal variation in PEF on the third day was 7.23 +/- 3.48 (A%M) and 2.98 +/- 1.31 (SD%M). Both the diurnal variation and the calculated upper limits of normality were found to be lower than those reported previously for Western subjects. This knowledge of diurnal variation is important for any meaningful interpretation of PEF recordings used to monitor patients with asthma.
Adult↗
Reducing the number of daily measurements results in poor estimation of diurnal variability of peak expiratory flow in healthy individuals.
AIM: To determine the effect of reducing number of daily measurements on estimation of diurnal variability (DV) of peak expiratory flow (PEF). SUBJECTS AND METHODS: PEF was recorded five times daily for three days in 152 healthy adults. Amplitude percent mean (A%M) and standard deviation percent mean (SD%M) were calculated on third day from five, four, three and two daily readings. Proportion of variability explained by partial schedules was calculated and limits of agreement derived to assess if these methods could be used interchangeably. RESULTS: Four, three and two measurements explained 90-95%, 70-82% and 55% DV respectively using A%M. All schedules of partial measurement using SD%M explained >90% DV. Limits of agreement for A%M and SD%M widened as number of measurements were reduced. CONCLUSIONS: DV obtained by fewer daily measurements agrees poorly with results obtained from five measurements. SD%M is a better alternative if DV is assessed from fewer readings.
Adult↗