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Amplifications and target genes in diffuse large B-cell lymphoma: real targets or consequences of structural features of the genome?

The most frequent primary genetic alteration of the Bcell neoplasms are chromosomal translocations that activate oncogenes and are essential for tumor initiation, whereas gene amplification represents another mechanism of oncogene overexpression and is found as a secondary genetic alteration. B-cell lymphomas harboring amplifications show complex and numerous alterations and are associated with an aggressive clinical behavior [1]. Metaphaseand array-comparative genomic hybridization (CGH) techniques have been very useful as a genomic tool for the screening of high-level DNA amplifications. Nevertheless, most of the target genes still remain to be elucidated. In that sense, the use of CGH/array-CGH in diffuse large Bcell lymphoma (DLBCL) has allowed the identification of recurrent amplifications and target genes, namely BCL2 and MALT1 (18q21); REL and BCL11A (2p16); CDK4, MDM2, GLI, and SAS (12q13); MIRHG1 (microRNA-17-92 cluster) (13q31.3), JAK2 (9p24); MYC (8q24); RFC4 and BCL6 (3q27); and CCND3 and BYSL (6p21). However, there are still a large number of additional amplified regions in DLBCL with elusive target genes (1q21, 1q25–q31, 2q22–q24, 4p15, 5p15, 5q34, 6p25, 9q33–q34, 10p13–p15, 10q11, 11q22–q24, 16p12, 16q24, 17p11, 22q12, Xp22, and Xq28). In this issue of Leukemia and Lymphoma, Nagel et al. [2] identify the kinase SIK2 as a target of 11q23 amplification in a DLBCL cell line, Karpas422. Furthermore, the authors perform functional analyses which indicate that SIK2 regulates survival and glucose metabolism via the pro-apoptotic gene BIM, and discuss that SIK2 and its downstream effectors could represent potential novel therapeutic targets. Nevertheless, although the gain and occasional amplification of the 11q22–q24 region is found in *8–15% of DLBCL, SIK2 amplification and overexpression could only be demonstrated in this cell line. In addition, SIK2 overexpression could not be detected in any DLBCL primary tumors. Interestingly, a similar situation has been reported for homozygous deletions, where validated target genes have been identified only in cancer cell lines but not in human tumors of the same entity [3,4]. Conventional cytogenetics [5] and FISH analysis [6] of Karpas-422 have reported a complex derivative 11 chromosome formed through terminal deletion and four inverted tandem repeats. These results are fully concordant with the data generated by SNP-array 6.0 (www.sanger.ac.uk) and also by the polymerase chain reaction (PCR) results of Nagel et al.: four copies of 11q23, a peak of eight-fold amplification of SIK2 gene, and a terminal 11q24–q25 deletion. Of note, Karpas422 has a functionally inactivated TP53 gene (point mutation plus deletion), and most of the chromosomes showed multiple structural alterations, including another focal amplification in 16p. The loss of TP53 function is strongly associated with genomic instability in human tumors, and one of the manifestations of genomic instability is DNA amplification. One of the mechanisms proposed for gene amplification is the breakage–fusion–bridge (BFB) cycle, which requires two or more breaks: the first leads to a telomere loss and is responsible for the initiation of several rounds of amplification, whereas the second break takes place during cell