Rhabdoid tumors are aggressive pediatric malignancies for which, currently, there are no effective or standard treatment strategies. Rhabdoid tumors arise because of the loss of the tumor suppressor gene INI1. We have previously demonstrated that INI1 represses Cyclin D1 transcription in rhabdoid cells by directly recruiting histone deacetylase 1 complex to its promoter, leading to G 0-G1 arrest. Expression of Cyclin D1 overcomes cell cycle arrest mediated by INI1 and Cyclin D1 overexpression in human rhabdoid tumors is a common phenomenon. However, it is not clear whether Cyclin D1 is a critical downstream target of INI1 in vivo and whether the derepression of this gene is essential for rhabdoid tumorigenesis. To determine the requirement of Cyclin D1 for genesis of rhabdoid tumors in vivo, we developed Ini1 heterozygous mice by targeted disruption. We found that the tumors developed in these Ini1؉͞؊ mice are rhabdoid, defective for Ini1 protein, and like the human tumors, express Cyclin D1. We crossed Ini1؉͞؊ mice to Cyclin D1؊͞؊ mice and found that Ini1؉͞؊ mice with Cyclin D1 deficiency did not develop any spontaneous tumors, in contrast to the parental Ini1؉͞؊ mice. These results strongly support the hypothesis that Cyclin D1 is a key mediator in the genesis of rhabdoid tumors. Our results provide an in vivo proof of concept that drugs that target Cyclin D1 expression or activity could be potentially effective as novel therapeutic agents for rhabdoid tumors.INI1͞hSNF5 ͉ cell cycle ͉ atypical teratoid ͉ tumorigenesis R habdoid tumors, including malignant rhabdoid tumors of the kidneys (MRT) and atypical teratoid and rhabdoid tumors (AT͞RT) of the brain and soft tissues, are highly aggressive pediatric malignancies (1-3). Prognosis for infants with these tumors is poor and Ϸ80% of the children die within 1 yr of diagnosis despite intensive treatment. Chemotherapy is effective only transiently in some AT͞RT patients and the use of radiotherapy is limited in children under 3 yr of age because of subsequent neurological damage and because surgical resection is challenging (3). In the past several years, there has been significant progress in the cytogenetic and molecular genetic studies, which indicated that the majority of MRT and AT͞RT tumors harbor recurrent biallelic alterations in the INI1͞hSNF5 gene, located in chromosome 22q11.2 (4-6). Several studies support the model that INI1 is a tumor suppressor. Children who harbor germ-line constitutive mutation in one allele of INI1 develop MRT or AT͞RT when the second allele of INI1 is also mutated (5), and families who are carriers of a mutation in this gene are predisposed to rhabdoid syndrome (7). Furthermore, mice heterozygous for Ini1͞hSNF5 mutations develop rhabdoid tumors with a high frequency because of loss of heterozygosity at the Ini1 locus (8-10).INI1͞hSNF5 is a component of the chromatin-remodeling mammalian SWI͞SNF complex (11). Reintroduction of this gene into rhabdoid cell lines causes G 0 -G 1 arrest and affects the transcription of several cell c...
Regulatory elements located within a ~28 kb region 3′ of the Igh gene cluster (3′ regulatory region, 3′ RR) are required for class switch recombination and for high levels of IgH expression in plasma cells. We previously defined novel DNase I hypersensitive (hs) sites, i.e. hs5-7, immediately downstream of this region. Hs5-7 contains a high density of binding sites for CTCF, a zinc finger protein associated with mammalian insulator activity and is an anchor for interactions with CTCF sites flanking the DH region. To test the function of hs5-7, we have generated mice with an 8 kb deletion encompassing all three hs elements. B cells from hs5-7 KO mice showed a modest increase in expression of the nearest downstream gene. In addition, Igh alleles in hs5-7 KO mice were in a less contracted configuration compared to WT Igh alleles and showed a two-fold increase in the usage of proximal VH7183 gene families. Hs5-7 KO mice were essentially indistinguishable from wild type mice in B cell development, allelic regulation, class switch recombination, and chromosomal looping. We conclude that hs5-7--a high-density CTCF binding region at the 3′ end of the Igh locus--impacts usage of VH regions as far as 500 kb away.
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