Mlt/Malt1 Involving Translocations And Amplifications Are Important Mechanisms In The Pathogenesis Of Non-Hodgkin'S Lymphoma.

6582 Background: The t(11;18)(q21;q21) and the t(14;18)(q32;q21) involving the MLT/MALT1 gene are the main structural abnormalities in extranodal marginal zone lymphoma (MZL). In addition, amplification of MLT/MALT1 has been proposed as a pathogenetic mechanism in NHL. Amplifications in 18q21 frequently involve the BCL2 gene, which lies about 5Mb telomeric to MLT/MALT1. However, a recent study described amplification of MLT/MALT1 without BCL2 coamplification, suggesting that MLT/MALT1 and BCL2 are independent targets of amplification in NHL. Methods: In order to screen for translocations and amplifications of MLT/MALT1, we have analyzed 214 NHL with a novel FISH assay using probes flanking the MLT/MALT1 gene (PACs 117B5 and 59N7). The assay was applied to 91 MALT lymphomas, 19 splenic MZL, 17 nodal MZL, 17 follicular lymphomas (FL), 8 mantle cell lymphomas (MCL), 15 chronic lymphocytic leukemias (CLL), 3 B-cell prolymphocytic leukemias (PLL), 9 Burkitt’s lymphomas (BL), 30 diffuse large B-cell lymphomas (DLBCL), 5 T-cell NHL, and 10 cell lines (7 BL, 1 transformed MCL, 1 transformed FL, and 1 MZL). Results: In 20 MALT lymphomas (22% of MALT lymphomas) a translocation involving MLT/MALT1 was detected. FISH analyses with API2 and IGH specific probes revealed the t(11;18) in 13 cases and the t(14;18) in 7 cases. Amplification of MLT/MALT1 was observed in 2 DLBCL, the MZL cell line SSK41, and the BL cell line NAMALWA. Further FISH analyses showed a concomitant amplification of BCL2 in the 2 DLBCL but in SSK41 and NAMALWA an amplification of MLT/MALT1 without BCL2 involvement was found. Trisomy or polysomy of the chromosomal region 18q21 was found in 13 MZL, 9 DLBCL, 8 FL, 1 MCL, 1 CLL, and the transformed MCL cell line Granta-519. In addition, a heterozygous deletion of MLT/MALT1 was detected in two MALT lymphomas of the stomach. Conclusions: 1) MLT/MALT1 associated translocations occur exclusively in extranodal MALT lymphomas and represent either the t(11;18) or the t(14;18); 2) true amplifications of MLT/MALT1 occur in some aggressive NHL and some transformed cell lines; and 3) trisomy or polysomy of 18q21 are seen in different subtypes of B-cell NHL and cell lines. No significant financial relationships to disclose.