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| Status |
Public on Feb 20, 2013 |
| Title |
Xist RNA is a potent suppressor of hematologic cancer in mice. |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| 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 (HSC) 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 is not only required to maintain XCI but also suppresses cancer in vivo.
We carried out expression profiling in hematopoietic cells isolated from Xist-deficient female mice before disease (2 months old) and during myeloprolifeative neoplasm/myelodysplastic syndrome (MPN/MDS) and chronic myelomonocytic leukemia (CMML)-like disease (6 and 12 months old) and compared profiles of purified bone marow HSCs (KLS+CD34-), splenic B-cells (B220+), myeloid cells (CD11b+), and erythroid cells (Ter119+) against those of corresponding cell types from age-matched wild-type female mice.
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| Overall design |
We conditionally targeted Xist locus in the blood compartment of mice by crossing Xist2lox/2lox mice (129Sv/Jae; Csankovszki et al., 1999) with Vav.Cre mice (B6.Cg-Tg (Vav1-cre)A2Kio/J; Jackson Laboratory). We used hematopoietic cells that were isolated from Xist-deficient and wild-type female progeny to analyze changes in gene expression due to loss of Xist.
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| Contributor(s) |
Yildirim E, Kirby JE, Brown DE, Mercier FE, Sadreyev RI, Scadden DT, Lee JT |
| Citation(s) |
23415223 |
| Submission date |
Jan 31, 2013 |
| Last update date |
Jul 22, 2022 |
| Contact name |
Ruslan Sadreyev |
| E-mail(s) |
rsadreyev@mgh.harvard.edu
|
| Phone |
6176435697
|
| Organization name |
Harvard Medical School/ Mass General Hospital
|
| Street address |
185 Cambridge St
|
| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02114 |
| Country |
USA |
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| Platforms (1) |
| GPL6246 |
[MoGene-1_0-st] Affymetrix Mouse Gene 1.0 ST Array [transcript (gene) version] |
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| Samples (20)
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| GSM1075041 |
B cells from 6 mo old female Xist heterozygous (2lox/-) mutant |
| GSM1075042 |
Myeloid cells from 6 mo old female Xist heterozygous (2lox/-) mutant |
| GSM1075043 |
LSK+CD34- HSCs from 6 mo old female Xist heterozygous (2lox/-) mutant |
| GSM1075044 |
Erythroid cells from 6 mo old female Xist heterozygous (2lox/-) mutant |
| GSM1075045 |
B cells from 6 mo old female Xist wild-type (2lox/+) |
| GSM1075046 |
Myeloid cells from 6 mo old female Xist wild-type (2lox/+) |
| GSM1075047 |
LSK+CD34- HSCs from 6 mo old female Xist wild-type (2lox/+) |
| GSM1075048 |
Erythroid cells from 6 mo old female Xist wild-type (2lox/+) |
| GSM1075049 |
B cells from 2 mo old female Xist wild-type (2lox/+) |
| GSM1075050 |
Myeloid cells from 2 mo old female Xist wild-type (2lox/+) |
| GSM1075051 |
LSK+CD34- HSCs from 2 mo old female Xist wild-type (2lox/+) |
| GSM1075052 |
Erythroid cells from 2 mo old female Xist wild-type (2lox/+) |
| GSM1075053 |
B cells from 2 mo old female Xist heterozygous (2lox/-) mutant |
| GSM1075054 |
Myeloid cells from 2 mo old female Xist heterozygous (2lox/-) mutant |
| GSM1075055 |
LSK+CD34- HSCs from 2 mo old female Xist heterozygous (2lox/-) mutant |
| GSM1075056 |
Erythroid cells from 2 mo old female Xist heterozygous (2lox/-) mutant |
| GSM1075057 |
B cells from 12 mo old female Xist homozygous (-/-) mutant |
| GSM1075058 |
Myeloid cells from 12 mo old female Xist homozygous (-/-) mutant |
| GSM1075059 |
LSK+CD34- HSCs from 12 mo old female Xist homozygous (-/-) mutant |
| GSM1075060 |
Erythroid cells from 12 mo old female Xist homozygous (-/-) mutant |
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| Relations |
| BioProject |
PRJNA188228 |
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