Xist RNA Is a Potent Suppressor of Hematologic Cancer in Mice

Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA
Cell (Impact Factor: 32.24). 02/2013; 152(4):727-42. DOI: 10.1016/j.cell.2013.01.034
Source: PubMed


X chromosome aneuploidies have long been associated with human cancers, but causality has not been established. In mammals, X chromosome inactivation (XCI) is triggered by Xist RNA to equalize gene expression between the sexes. Here we delete Xist in the blood compartment of mice and demonstrate that mutant females develop a highly aggressive myeloproliferative neoplasm and myelodysplastic syndrome (mixed MPN/MDS) with 100% penetrance. Significant disease components include primary myelofibrosis, leukemia, histiocytic sarcoma, and vasculitis. Xist-deficient hematopoietic stem cells (HSCs) show aberrant maturation and age-dependent loss. Reconstitution experiments indicate that MPN/MDS and myelofibrosis are of hematopoietic rather than stromal origin. We propose that Xist loss results in X reactivation and consequent genome-wide changes that lead to cancer, thereby causally linking the X chromosome to cancer in mice. Thus, Xist RNA not only is required to maintain XCI but also suppresses cancer in vivo.

44 Reads
  • Source
    • "In addition, multiple functions have been proposed for YY1 in X inactivation, including Xist RNA localization (Jeon and Lee, 2011) and Xist transcription (Makhlouf et al., 2014). Whereas Xist is not essential for maintenance of gene repression in somatic cells (Brown and Willard, 1994), loss of Xist in mice has recently been shown to lead to Xi reactivation in blood cells and leukemia (Yildirim et al., 2013). A genetic screen for epigenetic modifiers in mice has identified the SmcHD1 gene, which is required for maintaining DNA methylation and repression of Xi-linked gene promoters (Blewitt et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: In mammals, the noncoding Xist RNA triggers transcriptional silencing of one of the two X chromosomes in female cells. Here, we report a genetic screen for silencing factors in X chromosome inactivation using haploid mouse embryonic stem cells (ESCs) that carry an engineered selectable reporter system. This system was able to identify several candidate factors that are genetically required for chromosomal repression by Xist. Among the list of candidates, we identify the RNA-binding protein Spen, the homolog of split ends. Independent validation through gene deletion in ESCs confirms that Spen is required for gene repression by Xist. However, Spen is not required for Xist RNA localization and the recruitment of chromatin modifications, including Polycomb protein Ezh2. The identification of Spen opens avenues for further investigation into the gene-silencing pathway of Xist and shows the usefulness of haploid ESCs for genetic screening of epigenetic pathways. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 07/2015; DOI:10.1016/j.celrep.2015.06.067 · 8.36 Impact Factor
  • Source
    • "which is important for X chromosome inactivation (Hern andez-Mu~ noz et al. 2005). As loss of X chromosome inactivation causes an MDSlike disease in mice (Yildirim et al. 2013), differential splicing of macro-H2A.1 could potentially be relevant to disease processes. Isoform switches, wherein a previously minor isoform becomes the major isoform, were relatively rare but did occur. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Whole-exome sequencing studies have identified common mutations affecting genes encoding components of the RNA splicing machinery in hematological malignancies. Here, we sought to determine how mutations affecting the 3' splice site recognition factor U2AF1 alter its normal role in RNA splicing. We find that U2AF1 mutations influence the similarity of splicing programs in leukemias, but do not give rise to widespread splicing failure. U2AF1 mutations cause differential splicing of hundreds of genes, affecting biological pathways such as DNA methylation (DNMT3B), X chromosome inactivation (H2AFY), the DNA damage response (ATR, FANCA), and apoptosis (CASP8). We show that U2AF1 mutations alter the preferred 3' splice site motif in patients, in cell culture, and in vitro. Mutations affecting the first and second zinc fingers give rise to different alterations in splice site preference and largely distinct downstream splicing programs. These allele-specific effects are consistent with a computationally predicted model of U2AF1 in complex with RNA. Our findings suggest that U2AF1 mutations contribute to pathogenesis by causing quantitative changes in splicing that affect diverse cellular pathways, and give insight into the normal function of U2AF1's zinc finger domains.
    Genome Research 09/2014; 25(1). DOI:10.1101/gr.181016.114 · 14.63 Impact Factor
  • Source
    • "Although histiocytic sarcoma has been reported in several strains of genetically engineered mice less than 12 months of age [50], [51], [46], the neoplasm has not been reported in mice as young as the huTLR7/8 mice described in this report (in which lesions were identified grossly as early as 3 weeks of age in BAC#1 mice). Also, involvement of the lung with overtly neoplastic cells or histiocytic accumulations in previous reports of histiocytic sarcoma is present in greater than 20% of cases [50], [46], but was not observed in any of the huTLR7/8 mice. "
    [Show abstract] [Hide abstract]
    ABSTRACT: A humanized TLR7/TLR8 transgenic mouse line was engineered for studies using TLR7/8 ligands as vaccine adjuvants. The mice developed a spontaneous immune-mediated phenotype prior to six months of age characterized by runting, lethargy, blepharitis, and corneal ulceration. Histological examination revealed a marked, multisystemic histiocytic infiltrate that effaced normal architecture. The histological changes were distinct from those previously reported in mouse models of systemic lupus erythematosus. When the mice were crossed with MyD88-/- mice, which prevented toll-like receptor signaling, the inflammatory phenotype resolved. Illness may be caused by constitutive activation of human TLR7 or TLR8 in the bacterial artificial chromosome positive mice as increased TLR7 and TLR8 expression or activation has previously been implicated in autoimmune disease.
    PLoS ONE 09/2014; 9(9):e107257. DOI:10.1371/journal.pone.0107257 · 3.23 Impact Factor
Show more


44 Reads
Available from