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PMID: 23415223 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Xist RNA is a potent suppressor of hematologic cancer in mice.

Cell ·Vol. 152 ·No. 4 ·2013-02-14 ·Pages 727-42

Yildirim E, Kirby JE, Brown DE, Mercier FE, Sadreyev RI, Scadden DT, Lee JT

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.

MeSH Terms
Animals Bone Marrow/physiopathology Female Genes, Lethal Genes, Tumor Suppressor Hematopoietic Stem Cells/metabolism Male Mice Myelodysplastic Syndromes/genetics Myeloproliferative Disorders/genetics Primary Myelofibrosis/genetics RNA, Long Noncoding/genetics Splenomegaly/metabolism X Chromosome Inactivation
Chemicals
RNA, Long Noncoding XIST non-coding RNA
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Yildirim Eda
Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA 02114, USA.
Kirby James E
Brown Diane E
Mercier Francois E
Sadreyev Ruslan I
Scadden David T
Lee Jeannie T
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2013.01.034
Published
2013-02-14
Pages
727-42
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC3875356
Subset
IM
Grants
Howard Hughes Medical Institute · United States
NHLBI NIH HHS · R01 HL044851 · United States
NHLBI NIH HHS · HL44851 · United States
CIHR · Canada
Databases
GEO
GSE43961
Corrections
CommentIn
PMID: 23446546
External Links
PubMed source DOI: 10.1016/j.cell.2013.01.034 PMC Full Text View journal details
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