Genome‐wide search for loss of heterozygosity in Burkitt lymphoma cell lines

Additional chromosomal abnormalities are currently detected in Burkitt's lymphoma. They play major roles in the progression of BL and in prognosis. The genes involved remain elusive. A whole-genome oligonucleotide array CGH analysis correlated with karyotype and FISH was performed in a set of 27 Burkitt's lymphoma-derived cell lines and primary tumors. More than half of the 145 CNAs<2 Mb were mapped to Mendelian CNVs, including GSTT1, glutathione s-transferase and BIRC6, an anti-apoptotic protein, possibly predisposing to some cancers. Somatic cell line-specific CNVs localized to the IG locus were consistently observed with the 244 K aCGH platform. Among 136 CNAs >2 Mb, gains were found in 1q (12/27), 13q (7/27), 7q (6/27), 8q(4/27), 2p (3/27), 11q (2/27) and 15q (2/27). Losses were found in 3p (5/27), 4p (4/27), 4q (4/27), 9p (4/27), 13q (4/27), 6p (3/27), 17p (3/27), 6q (2/27),11pterp13 (2/27) and 14q12q21.3 (2/27). Twenty one minimal critical regions (MCR), (range 0.04–71.36 Mb), were delineated in tumors and cell lines. Three MCRs were localized to 1q. The proximal one was mapped to 1q21.1q25.2 with a 6.3 Mb amplicon (1q21.1q21.3) harboring BCA2 and PIAS3. In the other 2 MCRs, 1q32.1 and 1q44, MDM4 and AKT3 appeared as possible drivers of these gains respectively. The 13q31.3q32.1 <89.58–96.81> MCR contained an amplicon and ABCC4 might be the driver of this amplicon. The 40 Kb 2p16.1 <60.96–61> MCR was the smallest gained MCR and specifically encompassed the REL oncogene which is already implicated in B cell lymphomas. The most frequently deleted MCR was 3p14.1 <60.43–60.53> that removed the fifth exon of FHIT. Further investigations which combined gene expression and functional studies are essential to understand the lymphomagenesis mechanism and for the development of more effective, targeted therapeutic strategies.

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“…Mutations in the P53 gene have been found in at least 33% of BL biopsy specimens [51] and in as much as 83% of BL cell lines [52], [53].…”

Section: Discussionmentioning

confidence: 99%

High Resolution Genome-Wide Analysis of Chromosomal Alterations in Burkitt's Lymphoma

et al. 2009

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“…9 The human FCRL1 gene is located at chromosome region 1q21 where genome abnormalities including translocations frequently occur in various B-cell malignancies. [29][30][31] For FCRL5 (IRTA2), the expression levels are on average 10-fold higher in 1q21 abnormal cell lines. 8,32 In this study, high expression of FCRL1 expression on CLL cells was noticed.…”

Section: Discussionmentioning

confidence: 99%

FCRL1 on chronic lymphocytic leukemia, hairy cell leukemia, and B-cell non-Hodgkin lymphoma as a target of immunotoxins

Du¹,

Nagata²,

Ise³

et al. 2008

Blood

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“…19 As controls, we used the parent cell lines BJAB, 39,40 BL41, and DG75, which do not contain EBNA2-estrogen receptor transgene. Regarding the status of 1q21 aberrations, BJAB is not known to have any, 28 while BL41 does have limited 1q abnormalities which do not appear to include 1q21-25; 41 the status of 1q21 in DG75 cells is unknown. All cells were cultured in RPMI-1640 (HyClone, Logan, UT) containing 10% fetal bovine serum (HyClone), 2 M L-glutamine, 100 U/mL penicillin, 100 g/mL streptomycin, and nonessential amino acids.…”

Section: Cells and Cell Culturementioning

confidence: 99%

“…28 Furthermore, a genome-wide search for chromosomal abnormalities concluded that a gene important for Burkitt lymphoma pathogenesis is located in region 1q21-25, and overexpression of this gene mimics the effects of EBV. 41 As FcRH5 is encoded on 1q21 and is induced by EBV, FcRH5 is a candidate to be this unidentified gene. One can speculate that perturbation of FcRH5 expression and thus function during EBV-driven B-cell proliferation might disregulate B cells, thus contributing to B-cell malignancies.…”

Section: Ebna2 Induces Fcrh5 Expression Through Cbf1 4437mentioning

confidence: 99%

“…12,19,47 Alternatively, the lack of response in BL41-K3 cells may be secondary to aberrations of 1q21. 41 Of the 3 cell lines used, BJAB is not known to have any 1q21 abnormalities; 28 thus, it is a particularly suitable model to investigate the B-cell response to EBV. EBNA2 is known to down-regulate the immunoglobulin gene, 22 and LMP2A was proposed to take over B-cell-receptor signaling, 48 in which a role for induced FcRH5 remains to be established.…”

Section: Org Frommentioning

confidence: 99%

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Epstein-Barr virus nuclear antigen 2 induces FcRH5 expression through CBF1

Mohan

Dement-Brown

Maier

et al. 2006

Blood

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IntroductionEpstein-Barr virus (EBV) is a ␥-herpes virus with a widespread distribution in human populations. 1 EBV infects and immortalizes B cells and persists in the vast majority of individuals as a lifelong latent infection of the resting memory B-cell pool. 2 EBV is implicated in the etiology of a diverse range of malignancies, including Burkitt lymphoma, Hodgkin disease, and lymphomas that arise in immunosuppressed individuals. In addition, EBV is implicated in the development of a number of autoimmune diseases, including systemic lupus erythematosus. 3 EBNA2, together with EBNA-leader protein (LP), is the first viral gene expressed following infection and is absolutely required for B-cell transformation by initiating and maintaining proliferation. EBNA2 is a transcription factor with a potent transactivator domain, but without intrinsic DNA binding activity. EBNA2 is tethered to responsive viral and cellular promoters through host DNA-binding proteins, including CBF1 (also called RBP-J), 4-7 PU.1, 8 and hnRNP D. 9 EBNA2 initiates the transcription of a cascade of primary and secondary target genes that ultimately govern B-cell transformation. The relatively small group of proposed direct cellular target genes of EBNA2 includes CD23, 10 CD21, 11-13 C-MYC, 14 CCR7, 15 AML-2, 16 BATF, 17 and HES-1. 18 Of these, only CD23, AML-2, and C-MYC were conclusively demonstrated to be direct targets of EBNA2, as these genes did not require new protein synthesis for induction. Using a CBF1-deficient cell line, CD21 and CCR7 have recently been shown to strictly depend on CBF1 for induction by EBNA2. 19 AML-2, c-myc, BATF, and Hes-1 are all transcription factors, indicating there are likely to be numerous indirect targets of EBNA2. Indeed, among other genes, EBNA2 induces the tumor necrosis factor-␣ (TNF-a), cyclin D2, and interleukin-18 (IL-18) receptor genes indirectly. 20,21 In contrast, EBNA2 suppresses the transcription of the immunoglobulin (Ig) gene via CBF1-independent mechanisms. 19,22 EBNA2 is considered a viral analog of the cellular protein Notch. Accordingly, EBNA2 can functionally replace activated Notch. 23 All 4 Notch proteins interact with CBF1, and similarly to EBNA2 function by masking the transcriptional repressor domain of CBF1. [23][24][25] Not surprisingly, the target genes of EBNA2, at least partially, overlap with those of activated Notch. 17,26,27 Fc-receptor homolog (FcRH; also called immunoglobulin superfamily receptor translocation associated [IRTA]) comprises a family of 5 recently identified genes contiguously encoded on human chromosome 1q21. [28][29][30] Three mouse FcRHs have subsequently been identified, but there is considerable divergence from the human genes. 31 FcRH5 has no mouse homolog. The human FcRH genes are differentially expressed by specific B-cell subpopulations. 32,33 These genes encode transmembrane proteins with 3 to 9 Ig-like extracellular domains. All FcRH contain immunoreceptor tyrosine-based inhibitory motif (ITIM) and/or immunoreceptor tyrosine-based activation mot...

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Genome‐wide search for loss of heterozygosity in Burkitt lymphoma cell lines

Cited by 10 publications

References 30 publications

High Resolution Genome-Wide Analysis of Chromosomal Alterations in Burkitt's Lymphoma

High Resolution Genome-Wide Analysis of Chromosomal Alterations in Burkitt's Lymphoma

FCRL1 on chronic lymphocytic leukemia, hairy cell leukemia, and B-cell non-Hodgkin lymphoma as a target of immunotoxins

Epstein-Barr virus nuclear antigen 2 induces FcRH5 expression through CBF1

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