Disruption of Scaffold Attachment Factor B1 Leads to TBX2 Up-regulation, Lack of p19ARF Induction, Lack of Senescence, and Cell Immortalization

Dobrzycka, Klaudia M.; Kang, Kaiyan; Jiang, Shiming; Meyer, René; Rao, Pulivarthi H.; Lee, Adrian V.; Oesterreich, Steffi

doi:10.1158/0008-5472.can-06-1381

Cited by 17 publications

(16 citation statements)

References 22 publications

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“…Interestingly, among these were several genes with oncogenic potential, such as CDH3, TBX2, ERCC1, and NPR2 (Figure 2A-B), that have been reported to be involved in proliferation, tumor aggressiveness, and prognosis in a wide range of human cancers. 34,35 Interestingly, among these hypomethylated genes also appeared the HOXA9 gene, which was previously described to be protected from methylation by the MLL fusion itself. 36 Thus, the present study not only characterizes epigenetically down-regulated genes but also identifies protooncogenes that may be inappropriately expressed in t(4;11)-and t(11;19)-positive MLL-rearranged ALL in infants.…”

Section: Methylation Patterns In Mll-rearranged Infant 5495mentioning

confidence: 99%

Specific promoter methylation identifies different subgroups of MLL-rearranged infant acute lymphoblastic leukemia, influences clinical outcome, and provides therapeutic options

Stumpel

Schneider

Roon

et al. 2009

Blood

142

137

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MLL-rearranged infant acute lymphoblastic leukemia (ALL) remains the most aggressive type of childhood leukemia, displaying a unique gene expression profile. Here we hypothesized that this characteristic gene expression signature may have been established by potentially reversible epigenetic modifications. To test this hypothesis, we used differential methylation hybridization to explore the DNA methylation patterns underlying MLLrearranged ALL in infants. The obtained results were correlated with gene expression data to confirm gene silencing as a result of promoter hypermethylation. Distinct promoter CpG island methylation patterns separated different genetic subtypes of MLL-rearranged ALL in infants. MLL translocations t(4;11) and t(11;19) characterized extensively hypermethylated leukemias, whereas t(9;11)-positive infant ALL and infant ALL carrying wildtype MLL genes epigenetically resembled normal bone marrow. Furthermore, the degree of promoter hypermethylation among infant ALL patients carrying t(4; 11) or t(11;19) appeared to influence relapse-free survival, with patients displaying accentuated methylation being at high relapse risk. Finally, we show that the demethylating agent zebularine reverses aberrant DNA methylation and effectively induces apoptosis in MLLrearranged ALL cells. Collectively these data suggest that aberrant DNA methylation occurs in the majority of MLLrearranged infant ALL cases and guides clinical outcome. Therefore, inhibition of aberrant DNA methylation may be an important novel therapeutic strategy for MLL-rearranged ALL in infants. (Blood. 2009;114:5490-5498) IntroductionAlthough long-term survival rates in childhood acute lymphoblastic leukemia (ALL) exceed 80%, 1 the survival chances of infants (Ͻ 1 year of age) still range between 20% and 50%. 2 Approximately 80% of infants with ALL carry chromosomal translocations involving the MLL (mixed lineage leukemia) gene, 3 fusing the N-terminal portion of the MLL gene to the C-terminal region of one of its translocation partner genes. The most frequent MLL translocations among infant ALL patients are t(4;11), t(11;19), and t(9;11), 2,4 giving rise to the fusion proteins MLL-AF4, MLL-ENL, and MLL-AF9. These chimeric MLL fusion proteins exhibit pronounced transforming capacities 5 and independently contribute to an unfavorable prognosis. 2,6 As a member of the trithorax gene family, MLL is involved in transcriptional regulation. 7 Therefore, structural alterations of this gene may be expected to affect its function, presumably leading to transcriptional deregulation. Not surprisingly, in recent gene expression profiling studies, 8,9 the authors characterized MLL-rearranged ALL as a unique type of leukemia that is genetically clearly separable from other ALL subtypes. Because epigenetic modifications affect gene expression patterns, 10 we hypothesized that the specific gene expression profiles associated with MLL-rearranged infant ALL may well be driven by epigenetic changes, which recently have been established to play important role...

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Section: Methylation Patterns In Mll-rearranged Infant 5495mentioning

confidence: 99%

Specific promoter methylation identifies different subgroups of MLL-rearranged infant acute lymphoblastic leukemia, influences clinical outcome, and provides therapeutic options

Stumpel

Schneider

Roon

et al. 2009

Blood

142

137

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“…SAFB1 −/− males were sterile, hypogonadal and had low testosterone, whereas SAFB1 −/− female mice were subfertile with markedly decreased oestradiol and testosterone. Interestingly, fibroblasts derived from SAFB −/− embryos were found to be considerably more liable to lose senescence and acquire immortality than SAFB +/+ cells [108]. SAFB −/− knockout mice also show defects in the development of the haematopoietic system, with increased white blood cell counts and increased signs of infections [107].…”

Section: Safb Function In Vivo and Possible Roles In Human Diseasementioning

confidence: 99%

The increasing diversity of functions attributed to the SAFB family of RNA-/DNA-binding proteins

Norman

Rivers

Lee

et al. 2016

Biochemical Journal

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RNA-binding proteins play a central role in cellular metabolism by orchestrating the complex interactions of coding, structural and regulatory RNA species. The SAFB (scaffold attachment factor B) proteins (SAFB1, SAFB2 and SAFB-like transcriptional modulator, SLTM), which are highly conserved evolutionarily, were first identified on the basis of their ability to bind scaffold attachment region DNA elements, but attention has subsequently shifted to their RNA-binding and protein-protein interactions. Initial studies identified the involvement of these proteins in the cellular stress response and other aspects of gene regulation. More recently, the multifunctional capabilities of SAFB proteins have shown that they play crucial roles in DNA repair, processing of mRNA and regulatory RNA, as well as in interaction with chromatin-modifying complexes. With the advent of new techniques for identifying RNA-binding sites, enumeration of individual RNA targets has now begun. This review aims to summarise what is currently known about the functions of SAFB proteins.

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“…Mouse embryonic fibroblasts deficient in SAFB1 showed a lack of contact inhibition, increased foci formation, and increased oncogene-induced anchorage-independent growth. Interestingly, they also displayed significantly decreased senescence (22).…”

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confidence: 98%

SAFB1 Mediates Repression of Immune Regulators and Apoptotic Genes in Breast Cancer Cells

Hammerich-Hille

Kaipparettu

Tsimelzon

et al. 2010

Journal of Biological Chemistry

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The scaffold attachment factors SAFB1 and SAFB2 are paralogs, which are involved in cell cycle regulation, apoptosis, differentiation, and stress response. They have been shown to function as estrogen receptor corepressors, and there is evidence for a role in breast tumorigenesis. To identify their endogenous target genes in MCF-7 breast cancer cells, we utilized a combined approach of chromatin immunoprecipitation (ChIP)-on-chip and gene expression array studies. By performing ChIP-on-chip on microarrays containing 24,000 promoters, we identified 541 SAFB1/SAFB2-binding sites in promoters of known genes, with significant enrichment on chromosomes 1 and 6. Gene expression analysis revealed that the majority of target genes were induced in the absence of SAFB1 or SAFB2 and less were repressed. Interestingly, there was no significant overlap between the genes identified by ChIP-on-chip and gene expression array analysis, suggesting regulation through regions outside the proximal promoters. In contrast to SAFB2, which shared most of its target genes with SAFB1, SAFB1 had many unique target genes, most of them involved in the regulation of the immune system. A subsequent analysis of the estrogen treatment group revealed that 12% of estrogen-regulated genes were dependent on SAFB1, with the majority being estrogen-repressed genes. These were primarily genes involved in apoptosis, such as BBC3, NEDD9, and OPG. Thus, this study confirms the primary role of SAFB1/SAFB2 as corepressors and also uncovers a previously unknown role for SAFB1 in the regulation of immune genes and in estrogen-mediated repression of genes. The estrogen receptor ␣ (ER␣)3 plays a pivotal role in both normal and pathophysiological processes, such as osteoporosis and breast cancer (1). The transcriptional activity of ER␣ is not only regulated by its ligand estrogen but also through its interaction with cofactors, which can either enhance (coactivators) or repress (corepressors) its activity (2). Briefly, upon binding of its ligand, ER␣ undergoes major structural rearrangements leading to exposure of binding surfaces that subsequently results in facilitated recruitment of different coactivators, including histone acetyltransferases or histone methyltransferases, and proteins from the SWI/SNF chromatin remodeling complex (3). In the absence of ligand, recruitment of corepressors results in the creation of locally repressed chromatin, subsequently resulting in inhibition of transcription (4).Our group has identified the scaffold attachment factors SAFB1 and SAFB2 as ER␣ corepressors (5, 6). The two proteins are paralogs that share 74% similarity at the amino acid levels, with up to 98% in some functional domains (7). The genes reside in close proximity on chromosome 19p13.3, oriented in a head-to-head orientation, separated by an ϳ500-bp GC-rich promoter (6). The C termini of the proteins harbor a repression domain that can refer repression when transferred to a heterologous DNA-binding protein. This repression domain can be further defined into two ...

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Disruption of Scaffold Attachment Factor B1 Leads to TBX2 Up-regulation, Lack of p19ARF Induction, Lack of Senescence, and Cell Immortalization

Cited by 17 publications

References 22 publications

Specific promoter methylation identifies different subgroups of MLL-rearranged infant acute lymphoblastic leukemia, influences clinical outcome, and provides therapeutic options

Specific promoter methylation identifies different subgroups of MLL-rearranged infant acute lymphoblastic leukemia, influences clinical outcome, and provides therapeutic options

The increasing diversity of functions attributed to the SAFB family of RNA-/DNA-binding proteins

SAFB1 Mediates Repression of Immune Regulators and Apoptotic Genes in Breast Cancer Cells

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