Cloning of two candidate tumor suppressor genes within a 10 kb region on chromosome 13q14, frequently deleted in chronic lymphocytic leukemia

Liu, Yie; Corcoran, Martin; Rasool, Omid; Ivanova, Ganka; Ibbotson, Rachel; Grandér, Dan; Iyengar, Arati; Baranova, Anna; Kashuba, Vladimir I.; Merup, Mats; Wu, Xiushan; Gardiner, Anne; Müllenbach, Roman; Полтараус, А. Б.; Hultström, Anna Linda; Juliusson, Gunnar; Chapman, Robert M.; Tiller, Mary; Cotter, Finbarr E.; Gahrton, Gösta; Yankovsky, N. K.; Zabarovsky, Eugene R.; Einhorn, Stefan; Oscier, David

doi:10.1038/sj.onc.1201643

Cited by 193 publications

(199 citation statements)

References 15 publications

(19 reference statements)

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“…Ultimately, a 10 kb transcript-rich MDR including exons of two genes, DLEU1 and DLEU2, was identified. 9 Sequence mutations and aberrant methylation patterns in this region have not been observed. [10][11][12] The identification of the miR15a/16-1 microRNA cluster within this region was a pivotal observation, 13 and it is now clear that this cluster drives a lymphoproliferative phenotype in vivo.…”

Section: Introductionmentioning

confidence: 99%

13q deletion anatomy and disease progression in patients with chronic lymphocytic leukemia

et al. 2010

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Historically, genes targeted by recurrent chromosomal deletions have been identified within the smallest genomic region shared in all patients, the minimally deleted region (MDR). However, deletions this small do not occur in all patients and are a simplification of the impact larger heterogeneous deletions have during carcinogenesis. We use the example of 13q14 deletions in chronic lymphocytic leukemia to show that genes outside MDRs are associated with disease progression. Genomic profiling of 224 patients identified 205 copy number alterations on chromosome 13 in 132 cases. Deletions including DLEU2 were heterogeneous (845 Kb-96.2 Mb) and identified two breakpoint cluster regions within short interspersed nuclear elements proximal to DLEU2 and within long interspersed nuclear elements/L1 repeats distal to GUCY1B2. After defining a deletion class on the basis of size and location, we show that (a) at diagnosis, larger deletions (class II) were associated with a significantly increased risk of disease progression (odds ratio ¼ 12.3; P ¼ 0.005), (b) in progressive patients, class II deletions were enriched (P ¼ 0.02) and (c) this association was independent of IgVH mutational status, ZAP70 expression and ATM/TP53 deletion. Deletion of a 1 Mb gene cluster (48.2-49.2 Mb), including SETDB2, PHF11 and RCBTB1, was significantly associated (Po0.01) with disease progression. Here, we show that the deletion of genes outside MDRs can influence clinical outcome.

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Section: Introductionmentioning

confidence: 99%

13q deletion anatomy and disease progression in patients with chronic lymphocytic leukemia

et al. 2010

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“…Furthermore, our data confirms our previous description 12 of a more telomeric minimal deleted critical region. However, the Leu1 and Leu2 locus is very frequently involved as shown in the first study performed by Liu et al, 15 and in the present study where 12 out of 15 samples are heterozygously deleted. Potential significance of this discrepancy, correlated to the…”

Section: Resultsmentioning

confidence: 53%

“…[11][12][13][14] Transcription maps of these regions are under construction. [14][15][16] Two candidate genes, located just centromeric to D13S319 (Figure 1a), called Leu1 and Leu2 have been proposed as tumor suppressor genes involved in B-CLL since the first exon of any of these two genes was deleted in all cases of 13q14.3 loss examined. 15 …”

Section: Introductionmentioning

confidence: 99%

Exclusion of Leu1 and Leu2 genes as tumor suppressor genes in 13q14.3-deleted B-CLL

et al. 1999

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The chromosomal region 13q14.3 is frequently deleted in B cell chronic lymphocytic leukemia (B-CLL) and it is supposed that a tumor suppressor gene, involved in this leukemogenesis, is located in this area. The first exons of two genes, Leu1 and Leu2, mapped in a minimally deleted 13q14.3 region, are systematically lost in B-CLL sharing a 13q14.3 deletion. These two genes have been proposed as strong tumor suppressor gene candidates. However, in a study on 15 13q14.3 deleted B-CLL, we found three patients in which this critical region was not involved. Because of these results and that no mutations were detected on the two genes in a previous study, we think that Leu1 and Leu2 can be excluded as tumor suppressor genes.

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“…2 Three candidate tumour suppressor genes from 13q14.3 have been identified in this area to date. 15,16 The first gene described, Leu1, consists of two exons and has a predicted open reading frame encoding for a 72 amino acid peptide. The gene is located centromeric of D13S319, within the RMD described by Corcoran et al 1 and Kalachikov et al, 12 but outside the RMD described by Bouyge-Moreau et al 13 and Bullrich et al 14 Extensive sequence analysis has failed to detect mutations in the genomic sequence of Leu1 in any CLL patients carrying heterozygous deletion of 13q14.3.…”

Section: Introductionmentioning

confidence: 99%

“…The gene is located centromeric of D13S319, within the RMD described by Corcoran et al 1 and Kalachikov et al, 12 but outside the RMD described by Bouyge-Moreau et al 13 and Bullrich et al 14 Extensive sequence analysis has failed to detect mutations in the genomic sequence of Leu1 in any CLL patients carrying heterozygous deletion of 13q14.3. 15,16 The second gene, Leu2, was also isolated from the same RMD. 1 This gene consists of two exons and has a predicted open reading frame encoding for an 84 amino acid protein.…”

Section: Introductionmentioning

confidence: 99%

Deletion analysis of chromosome 13q14.3 and characterisation of an alternative splice form of LEU1 in B cell chronic lymphocytic leukemia

et al. 2002

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Heterozygous and homozygous deletions of chromosome 13q14.3 are found in 50% of patients with B cell CLL, suggesting the presence of one or more tumour suppressor genes within the deleted region. To identify candidate genes from the region, we constructed a map of 13q14.3 using a combination of genomic and cDNA library screening. The incidence of deletions in CLL patients was 51.5% encompassing a 265 kb region of minimal deletion (RMD) telomeric to markers D13S319. Two CpG islands were identified within the RMD, the telomeric of which is fully methylated whilst the more centromeric is unmethylated. A novel transcript was identified within the RMD that represents an alternative splice version of Leu1. The nine exons of this transcript span a genomic of 436 kb with exon 1 of Leu1 being the common first exon. The remaining exons were shown to be more frequently deleted than Leu1 itself. All splice forms of this transcript were detectable by RT-PCR but Leu1 detected the most abundant message on Northern blotting. Sequence analysis failed to reveal inactivating mutations in patients with heterozygous deletion of 13q14.3, although a polymorphic T to A variant was identified within exon 1 of Leu1 in leukemic and normal controls. As no mutations have been detected for Leu1 or any other transcript so far described, we cannot exclude the existence of control elements within the RMD that may regulate expression of genes lying in this region.

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Cloning of two candidate tumor suppressor genes within a 10 kb region on chromosome 13q14, frequently deleted in chronic lymphocytic leukemia

Cited by 193 publications

References 15 publications

13q deletion anatomy and disease progression in patients with chronic lymphocytic leukemia

13q deletion anatomy and disease progression in patients with chronic lymphocytic leukemia

Exclusion of Leu1 and Leu2 genes as tumor suppressor genes in 13q14.3-deleted B-CLL

Deletion analysis of chromosome 13q14.3 and characterisation of an alternative splice form of LEU1 in B cell chronic lymphocytic leukemia

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