Detailed assessment of copy number alterations revealing homozygous deletions in 1p and 13q in mantle cell lymphoma

Thelander, Emma Flordal; Ichimura, Koichi; Collins, V. Peter; Walsh, Sarah H.; Barbany, Gisela; Hagberg, Anette; Laurell, Anna; Rosenquist, Richard; Lagercrantz, Svetlana

doi:10.1016/j.leukres.2006.10.022

Cited by 27 publications

(3 citation statements)

References 105 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…13q14 (region that encodes miR-15a/16-1 in humans) deletion is the most common chromosomal abnormality in CLL, occurring in 50–60% of patients [ 8 ]. It is believed to encode critical tumor suppressor genes since it is frequently deleted or silenced in various other malignancies like prostate cancer, mantle cell lymphoma, and multiple myeloma [ 9 – 11 ]. Detailed cytogenetic analysis has revealed the presence of a 130kb Minimal Deleted Region (MDR) centromeric to the marker D13S272 that contains several candidate tumor suppressor genes like Dleu1, Dleu2, Dleu5 and Dleu7 [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Therapeutic implications of activation of the host gene (Dleu2) promoter for miR-15a/16-1 in chronic lymphocytic leukemia

et al. 2013

View full text Add to dashboard Cite

Genetic lesions and other regulatory events lead to silencing of the 13q14 locus in a majority of chronic lymphocytic leukemia (CLL) patients. This locus encodes a pair of critical pro-apoptotic microRNAs, miR-15a/16-1. Decreased levels of miR-15a/16-1 are critical for the increased survival exhibited by CLL cells. Similarly, in a de novo murine model of CLL, the NZB strain, germline-encoded regulation of the syntenic region resulted in decreased miR-15a/16-1. In this paper we have identified additional molecular mechanisms regulating miR-15a/16-1 levels and shown that the transcription factor BSAP (B cell Specific Activator Protein) directly interacts with Dleu2, the host gene containing the mir-15a/16-1 loci and via negative regulation of the Dleu2 promoter results in repression of mir-15a/16 expression. CLL patient B cell expression levels of BSAP were increased compared to control sources of B cells. With the use of siRNA mediated repression, the levels of BSAP were decreased in vitro in the NZB derived malignant B1 cell line, LNC, and in ex vivo CLL patient PBMC. BSAP knockdown led to an increase in the expression of miR-15a/16-1 and an increase in apoptosis and a cell cycle arrest in both the cell line and patient PBMC. Moreover, using Dleu2 promoter analysis by chromatin immunoprecipitation (ChIP) assay we have shown that BSAP directly interacts with the Dleu2 promoter. Derepression of the Dleu2 promoter via inhibition of histone deacetylation combined with BSAP knockdown increased miR-15a/16 expression and increased malignant B cell death. In summary, therapy targeting enhanced host gene Dleu2 transcription may augment CLL therapy.

show abstract

Section: Introductionmentioning

confidence: 99%

Therapeutic implications of activation of the host gene (Dleu2) promoter for miR-15a/16-1 in chronic lymphocytic leukemia

et al. 2013

View full text Add to dashboard Cite

show abstract

“…To that end, a series of gene function-oriented publications including our own have identified chromosomal abnormalities that may have pathogenetic relevance(9). For example, deletions of 6q are a frequent observation in systemic DLBCL and are typically associated with a worse prognosis(10, 11).…”

Section: Introductionmentioning

confidence: 99%

Primary Central Nervous System Lymphomas: A Validation Study of Array-Based Comparative Genomic Hybridization in Formalin-Fixed Paraffin-Embedded Tumor Specimens

Braggio

McPhail

Macon

et al. 2011

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose Only a limited number of genetic studies have been performed in primary central nervous system lymphomas (PCNSL), partly due to the rarity of the tumors and the very limited amount of available tissue. In this report, we present the first molecular characterization of copy-number abnormalities (CNA) of newly diagnosed PCNSL by array-based comparative genomic hybridization in formalin fixed paraffin embedded (FFPE) specimens and compare the results with matched frozen tumor specimens. Experimental design We performed array-based comparative genomic hybridization (aCGH) in FFPE tissues from PCNSL. Results were compared with matched paired frozen tumors. Results Our analysis confirmed the good to fair quality and reliability of the data generated from limited amounts of tumoral FFPE tissue. Overall, all PCNSL cases were characterized by highly complex karyotypes with a median of 23 copy-number abnormalities (CNA) per patient (range 17–47). Overall, 20 chromosomal regions were recurrently found in more than 40% of cases. Deletions of 6p21, 6q, 9p21.3 and gain of 12q12-q24.33 were the commonest CNA. Other minimal affected regions were defined, and novel recurrent CNAs affecting single genes were identified in 3q26.32 (TBL1XR1) and 8q12.1 (TOX). Conclusions The results obtained are encouraging. Larger archival tissue collections can now be analyzed in order to complement the still fragmented knowledge we have of the genetic basis of the PCNSL.

show abstract

“…However, the most common chromosomal abnormality observed in CLL patients (50-60%) is 13q14 deletion (contains miR15a/16-1) (Dohner et al, 2000). This region is also deleted in 50% of Mantle Cell Lymphomas and 40% of Multiple Myeloma indicating that it harbors critical tumor suppressor genes (Chang et al, 2004, Chen et al, 2007, Flordal Thelander et al, 2007. Detailed characterization of the 13q region in CLL patients led to the discovery of a 130kb Minimal Deleted Region (MDR) centromeric to the marker D13S272 (Corcoran et al, 1998, Migliazza et al, 2001.…”

Section: Genetic Abnormalities In Cllmentioning

confidence: 99%

Altering microRNA miR15a/16 Levels as Potential Therapy in CLL: Extrapolating from the De Novo NZB Mouse Model

Kasar¹,

Yao²,

Underbayev³

et al. 2012

Chronic Lymphocytic Leukemia

View full text Add to dashboard Cite

Detailed assessment of copy number alterations revealing homozygous deletions in 1p and 13q in mantle cell lymphoma

Cited by 27 publications

References 105 publications

Therapeutic implications of activation of the host gene (Dleu2) promoter for miR-15a/16-1 in chronic lymphocytic leukemia

Therapeutic implications of activation of the host gene (Dleu2) promoter for miR-15a/16-1 in chronic lymphocytic leukemia

Primary Central Nervous System Lymphomas: A Validation Study of Array-Based Comparative Genomic Hybridization in Formalin-Fixed Paraffin-Embedded Tumor Specimens

Altering microRNA miR15a/16 Levels as Potential Therapy in CLL: Extrapolating from the De Novo NZB Mouse Model

Contact Info

Product

Resources

About