title: Xist RNA is a potent suppressor of hematologic cancer in mice.
abstract: 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.
authors: Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Eda
authors: E
authors: Yildirim
authors: James E
authors: JE
authors: Kirby
authors: Diane E
authors: DE
authors: Brown
authors: Francois E
authors: FE
authors: Mercier
authors: Ruslan I
authors: RI
authors: Sadreyev
authors: David T
authors: DT
authors: Scadden
authors: Jeannie T
authors: JT
authors: Lee
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000503:physiopathology; D005260:Female; D005804:Genes, Lethal; D016147:Genes, Tumor Suppressor; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D008297:Male; D051379:Mice; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D009196:Myeloproliferative Disorders / Q000235:genetics*; D055728:Primary Myelofibrosis / Q000235:genetics; D062085:RNA, Long Noncoding / Q000235:genetics*; D013163:Splenomegaly / Q000378:metabolism; D049951:X Chromosome Inactivation
chemical_list: D062085:RNA, Long Noncoding; C077885:XIST non-coding RNA