Xist RNA Is a Potent Suppressor of Hematologic Cancer in Mice

Abstract

SUMMARY 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.

The lncRNA XIST exhibits oncogenic properties via regulation of miR-449a and Bcl-2 in human non-small cell lung cancer

“…A previous study showed that XIST downregulation exerts tumorsuppressive functions by reducing cell proliferation, migration, and invasion as well as inducing apoptosis in GSCs [17] . While XIST has been reported to be a potent suppressor of hematological cancer [26] , our results revealed that knockdown of XIST promotes NSCLC cell apoptosis and inhibits cell proliferation, migration and invasion. The in vivo studies demonstrated that XIST downregulation suppresses tumor growth.…”

“…All of these data indicate that XIST plays an important role in the development of NSCLC. However, XIST repression may hinder pluripotent stem cell induction at early stages in women [27] and might be critical for the long-term survival of stem cells [26] . Hence, XIST is associated with the evolution of cancer stem cells to tumor cells.…”

Sexual dimorphism in cancer

“…Although inactivation of one X chromosome over the other is generally random, preferential inactivation of one chromosome (skewed Xi) can protect women against the consequences of X-linked gene mutations 104 . On the contrary the absence of Xi can have detrimental effects: for instance loss of Xist has been reported in breast, ovarian and cervical cancer cell lines 105,106 and, only in female mutant mice, it caused deregulation of hematopoietic lineages and emergence of myeloid neoplasms associated with genome wide changes in gene expression 107 .…”

Epigenetics: from the past to the present

“…Similarly, other genes for lncRNAs are part of the Xic: Tsix, Jpx, Ftx, Xite, RepA and Tsx; they regulate Xist expression (Yamada & Ogawa 2015). In a recent study, Yildirim et al (2013) showed that deletion of Xist induces an aggressive and lethal blood cancer in female mice. This result indicates that XiRNA also has an important role in cancer suppression (Yildirim et al 2013).…”

“…In a recent study, Yildirim et al (2013) showed that deletion of Xist induces an aggressive and lethal blood cancer in female mice. This result indicates that XiRNA also has an important role in cancer suppression (Yildirim et al 2013).…”