cDNA sequence and genomic structure of EVI2B, a gene lying within an intron of the neurofibromatosis type 1 gene

Cawthon, Richard M.; Andersen, Lone B.; Buchberg, Arthur M.; Xu, Guangwen; O’Connell, P.; Viskochil, David; Weiss, Robert B.; Wallace, Margaret R.; Marchuk, Douglas A.; Culver, Melanie; Stevens, Jeffrey C.; Jenkins, Nancy A.; Copeland, Neal G.; Collins, Francis S.; White, Ray

doi:10.1016/0888-7543(91)90410-g

Cited by 102 publications

(52 citation statements)

References 61 publications

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“…18,19 EBI2B lies within an intron of the neurofibromatosis type 1 tumor suppressor gene and is expressed in a number of different cell types, including myeloid cells. 20,21 EVI2B is also located within EVI2, a common viral integration site identified in retrovirus-induced myeloid tumors. 22 It has been speculated that viral integration at EVI2 alters the expression of EVI2B and that this altered expression predisposes mice to myeloid tumor development.…”

Section: Discussionmentioning

confidence: 99%

Distinct gene expression profiling in chronic lymphocytic leukemia with 11q23 deletion

et al. 2001

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Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with regard to its clinical course. The limitations of the methods currently available for prognostic assessment in CLL do not allow accurate prediction of the risk of disease progression in individual patients. The recently developed cDNA array technique provides a unique opportunity to study gene expression in various malignancies. To identify new molecular markers for prognostication of CLL patients, we analyzed cDNA arrays by using hierarchical clustering and standard statistic t-test on 34 CLL patients. We found significant expression differences in 78 genes compared to the reference tonsillar B lymphocytes. A cluster of genes, LCP1, PARP, BLR1, DEK, NPM, MCL1, SLP76, STAM, HIVEP1, EVI2B, CD25, HTLF, HIVEP2, BCL2, MNDA, PBX3, EBI2, TCF1, CGRP, CD14, IL8, GZMK, GPR17 and CD79B, was associated (P Ͻ 0.05) with the unfavorable 11q deletion and also with the unfavorable Binet stages B and C. We present here gene expression profiling that is associated with CLL patients with the 11q23 deletion. Many of the genes in the cluster have not previously been shown to be related to the initiation or progression of CLL. These novel findings provide fundamental information for further attempts to understand the interaction of the clustered genes in the leukomogenesis of CLL in order to better design treatments aimed at specific molecular target(s). Leukemia (2001) 15, 1721-1728.

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Section: Discussionmentioning

confidence: 99%

Distinct gene expression profiling in chronic lymphocytic leukemia with 11q23 deletion

et al. 2001

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“…While most of the common sites of viral integration identified in BXH-2 mice are thought to activate the expression of dominant protooncogenes (16,23,25,26), one notable exception has been the identification of a common site of viral integration which inactivates the tumor suppressor gene, Nf1. This common site of viral integration, named Evi2 (ectotropic viral integration 2), was identified in 10 to 15% of BXH-2 tumors and found to be within a large intron of the Nf1 gene (6,8). Using BXH-2 tumors in which biallelic Evi2 integrations had occurred, it was shown that the presence of the virus resulted in premature truncation of the Nf1 transcript, such that no full-length product could be produced (6,21).…”

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confidence: 99%

Retroviral Integration at the Epi1 Locus Cooperates with Nf1 Gene Loss in the Progression to Acute Myeloid Leukemia

Blaydes

Kogan

Truong

et al. 2001

J Virol

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Juvenile myelomonocytic leukemia (JMML) is a disease that occurs in young children and is associated with a high mortality rate. In most patients, JMML has a progressive course leading to death by virtue of infection, bleeding, or progression to acute myeloid leukemia (AML). As it is known that children with neurofibromatosis type 1 syndrome have a markedly increased risk of developing JMML, we have previously developed a mouse model of JMML through reconstitution of lethally irradiated mice with hematopoietic stem cells homozygous for a loss-of-function mutation in the Nf1 gene (D. L. Largaespada, C. I. Brannan, N. A. Jenkins, and N. G. Copeland, Nat. Genet. 12:137-143, 1996). In the course of these experiments, we found that all these genetically identical reconstituted mice developed a JMML-like disorder, but only a subset went on to develop more acute disease. This result strongly suggests that additional genetic lesions are responsible for disease progression to AML. Here, we describe the production of a unique tumor panel, created using the BXH-2 genetic background, for identification of these additional genetic lesions. Using this tumor panel, we have identified a locus, Epi1, which maps 30 to 40 kb downstream of the Myb gene and appears to be the most common site of somatic viral integration in BXH-2 mice. Our findings suggest that proviral integrations at Epi1 cooperate with loss of Nf1 to cause AML.Juvenile myelomonocytic leukemia (JMML) is a disease characterized by a young age of onset, a tendency to affect boys, prominent enlargement of the liver and spleen, leukocytosis, and the absence of the Philadelphia chromosome. JMML has a poor prognosis, with either progression to acute myeloid leukemia (AML) or death from bleeding or infection (36). It has been estimated that at least 10% of children with JMML also have neurofibromatosis type 1 (NF1) syndrome, an autosomal dominant disorder found in 1/3500 individuals (1,7,14,32). However, the actual frequency of children with NF1 and JMML is likely higher than 10% as the peak incidence of childhood leukemia occurs at an age when NF1 often goes undiagnosed (13, 34). In fact, one study found that 15% of JMML patients had mutations in the NF1 gene even though there was no previous clinical diagnosis of NF1 (33), suggesting that approximately 25% of JMML cases are associated with NF1.While RAS gene point mutations are commonly found in JMML patients without NF1, they are not found in JMML patients with NF1 (20), providing genetic evidence that NF1 and RAS are involved in the same pathway. This idea is supported by the fact that neurofibromin, the protein product of NF1, contains a region that has extensive homology with the catalytic domain of GTPase activating proteins that are known to accelerate the intrinsic GTPase activity of Ras, thereby negatively regulating Ras GTP levels (15). This suggests that inactivating mutations in NF1 are equivalent to activating mutations in RAS. Consistent with the hypothesis, analysis of bone marrow taken from children with ...

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“…Examples of genes within genes in the human genome have been described in the early 1990s within the human genes neurofibromatosis type I (NF1; Cawthon et al 1990Cawthon et al , 1991Viskochil et al 1991), retinoblastoma susceptibility gene (RB; Herzog et al 1996), and blood clotting factor VIII (Levinson et al 1990(Levinson et al , 1992. In particular, intron 22 of the human blood clotting factor VIII gene contains a bidirectional CpG island from which two internal genes are transcribed in opposite directions, F8A (Levinson et al 1990) and F8B (Levinson et al 1992).…”

Section: Naturally Occurring Cis -Antisense Transcriptsmentioning

confidence: 99%

The silence RNA keeps: cis mechanisms of RNA mediated epigenetic silencing in mammals

Tufarelli

2005

Phil. Trans. R. Soc. B

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One of the fundamental questions of modern biology is to unravel how genes are switched on and off at the right time and in the correct tissues. It is well recognized that gene regulation depends on a dynamic balance between activating and repressing forces, and multiple mechanisms are involved in both gene silencing and activation. Work over the last decade has revealed that in some cases transcriptional silencing of specific genes is mediated by RNAs that specifically recruit repressing complexes to homologous DNA sequences. Examples of both cis and trans RNA driven transcriptional silencing have been reported. This review focuses on those examples of transcriptional gene silencing in which the RNA component seems to act uniquely in cis. Speculative models of how such cis acting transcripts may trigger transcriptional silencing are proposed. Future experimental testing of these and other mechanisms is important to gain a fuller understanding of how genes are regulated and to identify instances in which such mechanisms are defective, leading to disease. Understanding the basic molecular basis of these phenomena will provide us with invaluable tools for the future development of targeted therapies and drugs for those diseases in which they are faulty.

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cDNA sequence and genomic structure of EVI2B, a gene lying within an intron of the neurofibromatosis type 1 gene

Cited by 102 publications

References 61 publications

Distinct gene expression profiling in chronic lymphocytic leukemia with 11q23 deletion

Distinct gene expression profiling in chronic lymphocytic leukemia with 11q23 deletion

Retroviral Integration at the Epi1 Locus Cooperates with Nf1 Gene Loss in the Progression to Acute Myeloid Leukemia

The silence RNA keeps: cis mechanisms of RNA mediated epigenetic silencing in mammals

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