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Xist RNA Is a Potent Suppressor of Hematologic Cancer in Mice
Ist Teil von
Cell, 2013-02, Vol.152 (4), p.727-742
Ort / Verlag
United States: Elsevier Inc
Erscheinungsjahr
2013
Quelle
MEDLINE
Beschreibungen/Notizen
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.
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► Deleting Xist causes blood cancer ► Overdosage of the X chromosome causes cancer ► Xist is required for hematopoietic stem cell survival and function ► Deleting Xist causes marrow fibrosis, leukemia, and histiocytic sarcoma
Deletion of Xist in the blood cells of female mice causes an aggressive and highly penetrant hematopoietic cancer.