Molecular analysis of the BCL-3 locus at chromosome 17q22 in B-cell neoplasms

Abstract

Abstract To better understand the role of the BCL-3 locus at chromosome 17q22 in the pathogenesis and progression of leukemias and lymphomas, we examined its genomic configuration in 264 B-cell malignancies and its expression in a smaller subset. Cases studied included 39 chronic lymphocytic leukemias, 58 low-grade follicular lymphomas, 20 mantle cell lymphomas, 30 small noncleaved cell lymphomas, 25 acute lymphoblastic leukemias, 10 acquired immunodeficiency syndrome--related non-Hodgkin's lymphomas, and 44 diffuse mixed- or diffuse large-cell lymphomas. In addition, 38 aggressive lymphomas (transformed follicular lymphomas) derived from previously indolent follicular lymphomas were examined. Southern blot analysis showed BCL-3 locus rearrangement in 4 cases (1.5%), ie, in 3 transformed follicular lymphomas and in 1 indolent follicular lymphoma. All 4 also had BCL-2 rearrangements consistent with their follicular center cell origin. None of the BCL-3 rearranged cases showed MYC gene rearrangement, as reported for the original leukemia that led to the discovery of BCL-3. Pretransformation specimens of all three transformed follicular lymphomas showed the presence of the BCL-3 alteration before histologic progression. In 1 case, serial pretransformation biopsies showed that the BCL-3 rearrangement was acquired during the indolent follicular phase of the patient's disease. Thirty lymphomas, including 2 of the 4 with BCL-3 rearrangement, were also examined for BCL-3 message. All 30, including the 2 with BCL-3 rearrangements, expressed the normal 1.7-kb BCL-3 transcript, at approximately equivalent levels. The data indicate that, although BCL-3 locus alterations are found in only a small fraction of B-cell lymphoid malignancies, they occur primarily in a subset of follicular center cell lymphomas. Interestingly, these alterations appear to be acquired during the indolent (follicular) phase of the disease and they are maintained when histologic transformation takes place. The data also suggest that BCL-3 locus alterations do not result in gross changes of BCL-3 gene expression and do not necessarily involve the MYC gene. Although the preferential involvement of BCL-3 alterations in a small subset of follicular lymphomas that transform suggests a possible link between these abnormalities and progression, further studies are needed to ensure that these alterations are biologically relevant and not simply a manifestation of genomic instability.