Comprehensive analysis of a large genomic sequence at the putative B-cell chronic lymphocytic leukaemia (B-CLL) tumour suppresser gene locus

Rondeau, Gaelle; Moreau, Isabelle; Bézieau, Stéphane; Petit, Jean-Louis; Heilig, Roland; Fernandez, Sylvaine; Pennarun, Erwan; Myers, Jeremy S.; Batzer, Mark A.; Moisan, Jean‐Paul; Devilder, Marie‐Claire

doi:10.1016/s0027-5107(01)00219-6

Cited by 20 publications

(16 citation statements)

References 23 publications

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“…And none of these known genes were found inactivated in CLL by mutations or deletions. [8][9][10][11] In 2001, we generated somatic cell hybrids between mouse and CLLs cells carrying 13q14 deletion and translocation. Analysis of these hybrids revealed that 13q14 tumor-suppressor gene lies within a 30-kb region between exons 2 and 5 of the DLEU2 gene ( Figure 1).…”

Section: Mir-15/16 At 13q14 Gene Discoverymentioning

confidence: 99%

Role of miR-15/16 in CLL

2014

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B-cell chronic lymphocytic leukemia (CLL) is the most common adult leukemia. The most common chromosomal abnormalities detectable by cytogenetics include deletion at 13q (55%), 11q (18%), trisomy 12 (12-16%) and 17p (8%). In 2002, we discovered that a microRNA cluster miR-15a/miR-16-1 (miR-15/16) is the target of 13q deletions in CLL. MicroRNAs encoded by the miR-15/16 locus (miR-15 and miR-16) function as tumor suppressors. Expression of these miRNAs downregulated in CLL, melanoma, colorectal cancer, bladder cancer and other solid tumors. miR-15/16 cluster targets multiple oncogenes, including BCL2, Cyclin D1, MCL1 and others. The most important target of miR-15/16 in CLL is arguably BCL2, as BCL2 is overexpressed in almost all CLLs. In this review, we discuss the discovery, functions, clinical relevance and treatment opportunities related to miR-15/16.

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Section: Mir-15/16 At 13q14 Gene Discoverymentioning

confidence: 99%

Role of miR-15/16 in CLL

2014

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“…The extensive characterization of 13q14 deletions has demonstrated that the break points are heterogenous and that the deleted region can comprise multiple genes. [10][11][12][13][14][15][16][17] These studies led to the identification of a minimal deleted region (MDR) 12,13 that comprises the deleted in leukemia 2 (DLEU2) gene encoding a sterile RNA transcript and the microRNA 15a/16-1 cluster 18 that is located in an intron of DLEU2 ( Figure 1); this DLEU2/miR-15a/ 16-1 locus is invariably affected by deletions in all CLL with 13q14 aberrations. Functional evidence has long suggested an involvement of miR-15a/16-1 deletion in CLL development, [19][20][21] and the causative role of miR-15a/16-1 in CLL pathogenesis has been demonstrated recently in vivo in a knockout mouse model in which these microRNAs were specifically deleted in B cells.…”

Section: Introductionmentioning

confidence: 99%

Functional dissection of the chromosome 13q14 tumor-suppressor locus using transgenic mouse lines

Lia

Carette²,

Tang

et al. 2012

Blood

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“…Efforts by multiple groups have identified candidate genes within an f1 Mb stretch on chromosome 13 that have each been implicated in CLL del13q14 biology; nonetheless, mutations in these genes have not been identified and questions remain as to the validity of reducing the biology of del13q14 to a minimal deleted region or a single-gene mutation/expression event (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Analysis of del13q14 is further complicated by an evolving understanding of resident gene structure and the discovery of complex noncoding RNAs (20).…”

Section: Introductionmentioning

confidence: 99%

Integrated Genomic Profiling of Chronic Lymphocytic Leukemia Identifies Subtypes of Deletion 13q14

et al. 2008

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Chronic lymphocytic leukemia (CLL) is a biologically heterogeneous illness with a variable clinical course. Loss of chromosomal material on chromosome 13 at cytoband 13q14 is the most frequent genetic abnormality in CLL, but the molecular aberrations underlying del13q14 in CLL remain incompletely characterized. We analyzed 171 CLL cases for loss of heterozygosity and subchromosomal copy loss on chromosome 13 in DNA from fluorescence-activated cell sorting-sorted CD19 + cells and paired buccal cells using the Affymetrix XbaI 50k SNP array platform. The resulting highresolution genomic maps, together with array-based measurements of expression levels of RNA in CLL cases with and without del13q14 and quantitative PCR-based expression analysis of selected genes, support the following conclusions: (a) del13q14 is heterogeneous and composed of multiple subtypes, with deletion of Rb or the miR15a/miR16 loci serving as anatomic landmarks, respectively; (b) del13q14 type Ia deletions are relatively uniform in length and extend from breakpoints close to the miR15a/miR16 cluster to a newly identified telomeric breakpoint cluster at the f50.2 to 50.5 Mb physical position; (c) LATS2 RNA levels are f2.6-fold to 2.8-fold lower in cases with del13q14 type I that do not delete Rb, as opposed to del13q14 type II or all other CLL cases; (d) PHLPP RNA is absent in f50% of CLL cases with del13q14; and (e) f15% of CLL cases display marked reductions in miR15a/miR16 expression that are often but not invariably associated with bi-allelic miR15a/miR16 loss. These data should aid future investigations into biological differences imparted on CLL by different del13q14 subtypes.

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Comprehensive analysis of a large genomic sequence at the putative B-cell chronic lymphocytic leukaemia (B-CLL) tumour suppresser gene locus

Cited by 20 publications

References 23 publications

Role of miR-15/16 in CLL

Role of miR-15/16 in CLL

Functional dissection of the chromosome 13q14 tumor-suppressor locus using transgenic mouse lines

Integrated Genomic Profiling of Chronic Lymphocytic Leukemia Identifies Subtypes of Deletion 13q14

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