Characterization of a novel B‐CLL candidate gene – DLEU7 – located in the 13q14 tumor suppressor locus

Abstract

Deletion of chromosome 13q14 is the most frequent genetic aberration in B-cell chronic lymphocytic leukemia (CLL), found in more than 50% of cases, indicating that this region contains a gene(s) involved in the development of CLL. However, the pathogenic gene in the critical 13q14 region has not yet been de¢ned. Here, we have cloned and characterized a novel gene, DLEU7, located adjacent to the consensus deleted region, and overlapping the 3P P end of DLEU1 tail to tail. Human DLEU7 encodes a putative 221 amino acid protein, with signi¢cant conservation in rodents. Mutational and expression analysis in primary CLL samples failed to demonstrate any speci¢c mutations in DLEU7, but no DLEU7 expression could be detected in CLL cells. Methylation of a CpG island in the promoter region of DLEU7 was further analyzed as a possible mechanism for the absence of DLEU7 expression, and the promoter was found to be methylated in the majority of the CLL samples investigated.

Array CGH demonstrates characteristic aberration signatures in human papillary thyroid carcinomas governed by RET/PTC

“…It is of note that 21 tumour-suppressor genes map within either the specific or the consistently altered regions. TIMP3 and PTEN have already been reported as tumour suppressors in thyroid tumours (Hu et al, 2006;Hou et al, 2007;Wang et al, 2007), while others are involved in a variety of different tumour types, for example, TGFBR3 and ANXA7 in prostate cancer (Torosyan et al, 2006;Dong et al, 2007), TNFSF15 and TUSC1 in lung cancer (Shan et al, 2004;Hou et al, 2005), SYK and Net1 in breast cancer (Repana et al, 2006;Huang et al, 2007), SLIT1, RSU1 and KLF6 in gliomas and glioblastosmas (Chunduru et al, 2002;Dickinson et al, 2004;Camacho-Vanegas et al, 2007), DBC1 in bladder cancer (Louhelainen et al, 2006), DEC1 in oesophageal squamous cell carcinomas (Yang et al, 2005), RB1 in retinoblastoma (Corson and Gallie, 2007) and LATS2 and DLEU7 in leukaemias (Hammarsund et al, 2004;Jimenez-Velasco et al, 2005). Some of these tumour suppressors have influence on the regulation of chromatin acetylation …”

Role of miR-15/16 in CLL

“…35 Interestingly, in addition to miR-15/16, this region also contained DLEU7 gene (that was previously identified as a candidate tumor-suppressor gene at 13q14) located telometic to miR-15/16. 35, 36 We investigated whether DLEU7 can also function as a tumor suppressor and cooperate with miR-15/16, 37 as DLEU7 is the only protein-coding gene located within reported deleted region. Among the 25 CLL samples examined for DLEU7 expression, 24 showed lower expression compared with normal CD19 þ B cells, while 13 of the 25 samples showed decreases of Z10-fold.…”

Mantle cell lymphomas with clonal immunoglobulin V3–21 gene rearrangements exhibit fewer genomic imbalances than mantle cell lymphomas utilizing other immunoglobulin V genes

“…At present, a few candidate genes have been identified in the 13q14 region; however, it is not known if they are disease-related. 17,18 The presence of 13q14 deletions in both chronic lymphocytic leukemia and mantle cell lymphoma may indicate a common genetic component involved in the tumorigenesis of the two malignancies. Another possible mechanism is that different, but closely linked genes may be involved.…”

“…3 Characterization of variable heavy chain (V H ) gene usage has recently been performed in mantle cell lymphoma, revealing that two particular V H gene segments of the immunoglobulin (Ig) locus were preferentially used, namely V H 3-21 (18%) and V H 4-34 (16%). 2,6 Interestingly, the tumor samples with V H 3-21 gene usage almost exclusively expressed lambda light chains, and also in most cases utilized the same V l light chain gene (V l [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. 6 In addition, this group has been shown to have a significantly better prognosis in one report and in other studies displayed a clear tendency towards improved survival compared to mantle cell lymphomas utilizing other V H genes.…”