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

Rondeau, Gaelle; Moreau, Isabelle; Bézieau, Stéphane; Cadoret, Emmanuelle; Jp, Moisan; Mc, Devilder

doi:10.1038/sj.leu.2401525

Cited by 19 publications

(16 citation statements)

References 2 publications

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“…Two groups 23,26 reported exclusion of the EST70/Leu1 and 1B4/Leu2 genes from the deleted interval in 3 B-CLL cases when analyzing a total of 39 tumor samples with deletion at 13q14. However, this result was never observed by us and by 2 other groups 10,13,25 when mapping the deleted interval in more than 300 B-CLL samples with 13q14 deletion.…”

Section: Discussionmentioning

confidence: 99%

“…However, this result was never observed by us and by 2 other groups 10,13,25 when mapping the deleted interval in more than 300 B-CLL samples with 13q14 deletion. This discrepancy could either reflect different technical approaches used in mapping the deleted area (PCR 23,26 versus Southern blotting hybridization and/or fluorescence in situ hybridization 10,13,25 ) or point to the involvement of a second tumor suppressor locus in a small minority of B-CLL cases with deletion at 13q14.…”

Section: Discussionmentioning

confidence: 99%

“…10 This interval has also been confirmed by other studies. 13 In fact, the MDR exhibits a partial overlap with the regions of deletion as assigned in additional reports, [23][24][25][26] and it includes a locus of 10 kb that was previously defined as a minimal consensus for 13q14 deletion in B-CLL, based on the pattern of loss in 2 B-CLL cases and one cell line. 27 Here, we present the complete annotated sequence of approximately 347 kb encompassing the MDR and describe a complete characterization of the genes contained in this interval, an analysis of their expression status in B-CLL samples, and the screening of the entire MDR for mutations.…”

Section: Introductionmentioning

confidence: 99%

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Nucleotide sequence, transcription map, and mutation analysis of the 13q14 chromosomal region deleted in B-cell chronic lymphocytic leukemia

Migliazza

Bosch

Komatsu

et al. 2001

Blood

179

132

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IntroductionB-cell chronic lymphocytic leukemia (B-CLL) represents the most common leukemia in the Western countries with an estimated incidence of 1 per 100 000 per year. The disease is characterized by the monoclonal expansion of B lymphocytes expressing the CD5 marker and exhibiting a long life span, possibly because of a perturbed apoptotic program. 1 Current knowledge of the molecular pathogenesis of B-CLL is limited because no specific genetic alteration has yet been associated with this disease. In particular, B-CLL is not associated with reciprocal balanced chromosomal translocations. 2 Accordingly, none of the proto-oncogenes involved in chromosomal translocations in other mature B cell malignancies, including cyclin D1, 4 Although in a fraction of B-CLL cases, inactivation of the tumor suppressor gene p53 (on chromosome 17p13) and deletions or mutations of the ATM gene (on chromosome 11q22-23) have been reported, 5-9 such lesions were observed in late stages of the disease and may not represent primary tumorigenic events.Chromosome 13q14 deletions (approximately 50% of the patients) 2,10,11 are the commonest chromosomal alterations associated with B-CLL, followed by structural aberrations of chromosome 11q (19% of the cases) and trisomy of chromosome 12 (15%). 2 Moreover, chromosome 13 deletions can be the only cytogenetically detectable abnormality, suggesting an early role in B-CLL pathogenesis. Together, these findings point to the presence in this region of a tumor suppressor gene whose loss or inactivation may be crucial for the leukemogenesis.Deletions of chromosome 13q14 have also been reported in a variety of human tumors, including various other types of lymphoid tumors 12-17 and myeloid leukemias, 18 as well as prostate, 19,20 head and neck, 21 and non-small-cell lung cancers. 22 Although the deleted region of chromosome 13q14 has not yet been defined precisely in most of these neoplasms, these observations suggest that a common tumor suppressor gene may reside on this chromosomal segment.To identify the B-CLL-associated tumor suppressor gene, we previously constructed a high-density contiguous cosmid-based physical map encompassing the deleted interval. 10 This map allowed us to demonstrate that somatic loss at 13q14 occurs in 54% of the patients 10 (and unpublished results) and that the loss is monoallelic in 81% of such cases and biallelic in the remaining 19%. A minimal deleted region (MDR) in B-CLL, spanning less than 300 kilobase (kb) and representing the site of the B-CLLassociated putative tumor suppressor gene, was assigned on our For personal use only. on April 29, 2019. by guest www.bloodjournal.org From physical map in the interval between markers 173a12-82 and 138G4/1.3R. 10 This interval has also been confirmed by other studies. 13 In fact, the MDR exhibits a partial overlap with the regions of deletion as assigned in additional reports, [23][24][25][26] and it includes a locus of 10 kb that was previously defined as a minimal consensus for 13q14 deletion in B-CLL, based on the ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Nucleotide sequence, transcription map, and mutation analysis of the 13q14 chromosomal region deleted in B-cell chronic lymphocytic leukemia

Migliazza

Bosch

Komatsu

et al. 2001

Blood

179

132

View full text Add to dashboard Cite

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“…only 14 of the 50 exons of BCMS possess continuous ORF, and it is notable that no transcript was identified which consists only of a combination of these exons.' 41 Wolf and colleagues also carried out mutation analysis, but only applied to exons 17,28,29,33, and 40 of BCMS gene which corresponds to exons 3-7 of our clone 1 (see above) suggesting that despite the large number of additional exons, they also believed that these were genuine exons worthy of investigation.…”

Section: Figurementioning

confidence: 99%

“…Similar to analysis of Leu1, no mutations were demonstrated in 170 CLL patients, 15 and this gene has been excluded as a candidate tumor suppressor gene by some investigators. 17 A third gene, Leu5, (alternative name CAR) has also been described. 15,18 The deduced protein sequence of this gene shares significant homology with the RET finger protein and the well-known tumour suppressor gene BRCA1.…”

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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Delineation of the minimal region of loss at 13q14 in multiple myeloma

Elnenaei

Hamoudi

Swansbury

et al. 2002

Genes Chromosomes & Cancer

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Previous studies have focused on the incidence and prognostic implications of 13q14 deletions in multiple myeloma (MM), but none has sought to delineate the minimal common deleted region (CDR). In an effort to do so, dual-color interphase fluorescence in situ hybridization (FISH) was applied on 82 myeloma cases, initially by use of three probes for 13q14 (RB1, D13S319, and D13S25). Deletions were detected in 29/82 (35.4%) cases, and all except one were monoallelic. Subsequently, contiguous YACs, PACs, and a BAC spanning the 13q14-q21 region were employed for deletion mapping in addition to a 13q telomere probe. Large deletions extending to the 13q34 region were found in 55% of the deleted cases, whereas an additional 13.8% showed loss of both 13q34 and 13q14 regions with retention of 13q21. A CDR of approximately 350 kb was identified at 13q14 with the proximal border approximately 120 kb centromeric from D13S319, encompassing an area rich in expressed sequence tagged sites and containing DLEU1, DLEU2, and RFP2 genes. Direct sequencing of the RFP2 gene revealed no mutations in six patients and four MM cell lines harboring deletions of the CDR. However, a role for RFP2 in the pathogenesis of MM cannot yet be excluded, given that alternative mechanisms such as haploinsufficiency remain possible.

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

Cited by 19 publications

References 2 publications

Nucleotide sequence, transcription map, and mutation analysis of the 13q14 chromosomal region deleted in B-cell chronic lymphocytic leukemia

Nucleotide sequence, transcription map, and mutation analysis of the 13q14 chromosomal region deleted in B-cell chronic lymphocytic leukemia

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

Delineation of the minimal region of loss at 13q14 in multiple myeloma

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