B cell–derived chronic lymphocytic leukemia (B-CLL) represents a common malignancy whose cell derivation and pathogenesis are unknown. Recent studies have shown that >50% of CLLs display hypermutated immunoglobulin variable region (IgV) sequences and a more favorable prognosis, suggesting that they may represent a distinct subset of CLLs which have transited through germinal centers (GCs), the physiologic site of IgV hypermutation. To further investigate the phenotype of CLLs, their cellular derivation and their relationship to normal B cells, we have analyzed their gene expression profiles using oligonucleotide-based DNA chip microarrays representative of ∼12,000 genes. The results show that CLLs display a common and characteristic gene expression profile that is largely independent of their IgV genotype. Nevertheless, a restricted number of genes (<30) have been identified whose differential expression can distinguish IgV mutated versus unmutated cases and identify them in independent panels of cases. Comparison of CLL profiles with those of purified normal B cell subpopulations indicates that the common CLL profile is more related to memory B cells than to those derived from naive B cells, CD5+ B cells, and GC centroblasts and centrocytes. Finally, this analysis has identified a subset of genes specifically expressed by CLL cells of potential pathogenetic and clinical relevance.

A retrospective survey of patients with pathologically reviewed extragastric mucosa-associated lymphoma tissue (MALT) lymphomas from 20 institutions was performed. A total of 180 patients with histologically confirmed diagnosis of extragastric MALT lymphomas were studied. Their median age was 59 years (range, 21-92 years). Ann Arbor stage I disease was present in 115 patients (64%) and stage II disease in 16 (9%). Most cases were in the low or low-intermediate risk groups according to the International Prognostic Index (IPI). Forty-one (23%) patients had involvement of more than one extranodal site at diagnosis and in 24 cases (13%) the lymphoma presented at multiple mucosal sites (9 of them with only mucosal involvement, without bone marrow or nodal disease). Lymph node involvement was present in 21%. Patients were treated with a variety of therapeutic strategies, including chemotherapy in 78 cases. The median overall survival (OS) was not reached; the 5-year OS rate was 90% (95% CI, 82%-94%), the 5-year causespecific survival (CSS) was 94% (95% CI, 87%-97%), and the 5-year progressionfree survival (PFS) was 60% (95% CI, 50%-70%). Multivariate analysis showed that Ann Arbor stage was significantly associated with longer OS, nodal involvement with longer CSS, and favorable IPI score with better PFS. At a median follow-up of 3.4 years, 48 patients (27%; 95% CI, 20%-34%) had a relapse, 6 (3%; 95% CI, 1%-7%) showed histologic transformation, and 18 (10%; 95% CI, 6%-15%) experienced the development of a second tumor. Our data confirm the indolent nature of nongastric MALT lymphomas and the high rate of patients presenting with disseminated disease, which, when limited to mucosal sites, was not associated with a poorer outcome. (Blood. 2003;101: 2489-2495)

The molecular mechanism involved in the process of antigen-driven somatic hypermutation of Ig genes is unknown, but it is commonly believed that this mechanism is restricted to the Ig loci. B cell lymphomas commonly display multiple somatic mutations clustering in the 5 -regulatory region of BCL-6, a proto-oncogene encoding for a POZ͞Zinc finger transcriptional repressor expressed in germinal center (GC) B cells and required for GC formation. To determine whether BCL-6 mutations represent a tumor-associated phenomenon or ref lect a physiologic mechanism, we screened single human tonsillar GC B cells for mutations occurring in the BCL-6 5 -noncoding region and in the Ig variable heavy chain sequences. Thirty percent of GC B cells, but not naive B cells, displayed mutations in the 742 bp region analyzed within the first intron of BCL-6 (overall frequency: 5 ؋ 10 ؊4 ͞bp). Accordingly, an expanded survey in lymphoid malignancies showed that BCL-6 mutations are restricted to B cell tumors displaying GC or post-GC phenotype and carrying mutated Ig variable heavy chain sequences. These results indicate that the somatic hypermutation mechanism active in GC B cells physiologically targets non-Ig sequences.Somatic hypermutation is one of the mechanisms by which Ig genes are modified in B cells to generate a large repertoire of B lymphocytes, each expressing a unique antibody molecule (1). This process is activated in germinal center (GC) B cells (2-4), where it introduces mutations in the variable region of Ig genes (IgV) at a frequency of 2-8 ϫ 10 Ϫ2 in humans (5). The mechanism involved in IgV hypermutation is not known, although experimental evidence suggests that it requires transcription of the target sequences and the presence of the Ig enhancer but not a specific promoter (6-8).It is generally assumed that the process of somatic hypermutation is restricted to the Ig loci including heavy and light chain variable region genes (1). However, B cell lymphomas were shown to display somatic hypermutation of the 5Ј-noncoding region of BCL-6 (9, 10), a proto-oncogene encoding a POZ͞Zinc finger transcriptional repressor normally expressed within GC B cells and required for GC formation (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). In 30% of diffuse large cell lymphoma (DLCL) and 5-10% of follicular lymphoma (FL), the BCL-6 gene is altered structurally by chromosomal translocations (11). In addition, mutations of its 5Ј-noncoding region were frequently found in DLCL and FL even in the absence of translocations involving this locus (9, 10). In most tumor cases, mutations were multiple, often biallelic, and clustered in the 5Ј regulatory sequences at frequencies (7 ϫ 10 Ϫ4 through 1.6 ϫ 10 Ϫ2 ͞bp) comparable with that of IgV genes in B cells (9). These findings raised the question of whether BCL-6 mutations represent a tumor associated misfunction or the effect of the IgV hypermutation process acting on non-Ig genes.To address this issue, we have investigated the presence of BCL-6 mutations in normal GC and naive B cells by...

VMPT followed by VT as maintenance was superior to VMP alone in patients with multiple myeloma who are ineligible for autologous stem-cell transplantation.

Purpose In patients with myeloma, thalidomide significantly improves outcomes but increases the risk of thromboembolic events. In this randomized, open-label, multicenter trial, we compared aspirin (ASA) or fixed low-dose warfarin (WAR) versus low molecular weight heparin (LMWH) for preventing thromboembolism in patients with myeloma treated with thalidomide-based regimens. Patients and Methods A total of 667 patients with previously untreated myeloma who received thalidomide-containing regimens and had no clinical indication or contraindication for a specific antiplatelet or anticoagulant therapy were randomly assigned to receive ASA (100 mg/d), WAR (1.25 mg/d), or LMWH (enoxaparin 40 mg/d). A composite primary end point included serious thromboembolic events, acute cardiovascular events, or sudden deaths during the first 6 months of treatment. Results Of 659 analyzed patients, 43 (6.5%) had serious thromboembolic events, acute cardiovascular events, or sudden death during the first 6 months (6.4% in the ASA group, 8.2% in the WAR group, and 5.0% in the LMWH group). Compared with LMWH, the absolute differences were +1.3% (95% CI, −3.0% to 5.7%; P = .544) in the ASA group and +3.2% (95% CI, −1.5% to 7.8%; P = .183) in the WAR group. The risk of thromboembolism was 1.38 times higher in patients treated with thalidomide without bortezomib. Three major (0.5%) and 10 minor (1.5%) bleeding episodes were recorded. Conclusion In patients with myeloma treated with thalidomide-based regimens, ASA and WAR showed similar efficacy in reducing serious thromboembolic events, acute cardiovascular events, and sudden deaths compared with LMWH, except in elderly patients where WAR showed less efficacy than LMWH.