The BCL6 gene encodes a zinc-finger transcription factor and is altered by chromosomal rearrangements in its 5' noncoding region in '30% of diffuse large-cell lymphoma (DLCL). We report here that, in 22/30 (73%) DLCL and 7/15 (47%) follicular lymphoma (FL), but not in other tumor types, the BCL6 gene is also altered by multiple (1.4 x 10-3-1.6 x 10-2 per bp), often biallelic, mutations clustering in its 5' noncoding region. These mutations are of somatic origin and are found in cases displaying either normal or rearranged BCL6 alleles indicating their independence from chromosomal rearrangements and linkage to immunoglobulin genes. These alterations identify a mechanism of genetic instability in malignant B cells and may have been selected during lymphomagenesis for their role in altering BCL6 expression. Sequencing Procedures. PCR products E1.10, E1.11, and E1.12 were subjected to direct sequence analysis as described (21). In addition, a unique PCR product encompassing the same genomic region (nucleotides +413 to + 1141), amplified by primers E1.21C (upstream; 5'-ATGCTTTGGCTCCAA-GTT-3') and E1.26 (downstream; 5'-CACGATACTTCA-TCTCATC-3'), annealing temperature = 54°C, was subcloned into the pGEM-T vector (Promega), and DNA minipreps (Wizard DNA purification system, Promega) were sequenced using forward and reverse primers with the ABI373A DNA sequencer (Perkin-Elmer, Applied Biosystems Division).

LTHOUGH MYOCARDIAL INfarction (MI) and atherothrombotic ischemic stroke are thought to be caused by rupture of vulnerable atherosclerotic plaques, 1 they are recognized to be complex disorders that likely result from multifaceted interactions between an in

The locus for the cellular myc (c-myc) oncogene in humans is located on the region of chromosome 8 that is translocated to chromosome 14 in cells from most undifferentiated B-cell lymphomas. It is shown in this study that the c-myc locus is rearranged in 5 out of 15 cell lines from patients with undifferentiated B-cell lymphomas, and that the rearrangement involves a region at the 5' side of an apparently intact c-myc gene. In at least three patients, this rearranged region appears to contain immunoglobulin heavy chain mu sequences that are located on chromosome 14. The data indicate that this region contains the crossover point between chromosomes 8 and 14. The break point can occur at different positions on both chromosomes among individual cell lines.

Mutations of the ATM and NBS1 genes are responsible for the inherited Ataxia-Telangiectasia and Nijmegen Breakage Syndrome, both of which are associated with a predisposition to cancer. A related syndrome, the Ataxia-Telangiectasia-like disorder, is due to mutations of the MRE11 gene. However, the role of this gene in cancer development has not been established. Here we describe an often homozygous mutation of the poly(T)11 repeat within human MRE11 intron 4 that leads to aberrant splicing, impairment of wild-type MRE11 expression and generation of a truncated protein. This mutation is present in mismatch repair-deficient, but not proficient, colorectal cancer cell lines and primary tumours and is associated with reduced expression of the MRE11-NBS1-RAD50 complex, an impaired S-phase checkpoint and abrogation of MRE11 and NBS1 ionizing radiation-induced nuclear foci. Our findings identify MRE11 as a novel and major target for inactivation in mismatch repair-defective cells and suggest its impairment may contribute to the development of colorectal cancer.