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Cancer Cell. 2015 May 11;27(5):644-57. doi: 10.1016/j.ccell.2015.04.007.

Telomere dysfunction drives aberrant hematopoietic differentiation and myelodysplastic syndrome.

Author information

1
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: scolla@mdanderson.org.
2
Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
3
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
4
Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
5
Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
6
Department of Pediatric Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
7
Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Hematology, Department of Clinical and Experimental Medicine, University of Parma, 43126 Parma, Italy.
8
Hematology, Department of Clinical and Experimental Medicine, University of Parma, 43126 Parma, Italy.
9
Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
10
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
11
Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
12
In Silico Solutions, Falls Church, VA 22043, USA.
13
Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
14
Department of Hematopathology, University of Texas MD Cancer Center, Houston, TX 77030, USA.
15
Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: rdepinho@mdanderson.org.

Abstract

Myelodysplastic syndrome (MDS) risk correlates with advancing age, therapy-induced DNA damage, and/or shorter telomeres, but whether telomere erosion directly induces MDS is unknown. Here, we provide the genetic evidence that telomere dysfunction-induced DNA damage drives classical MDS phenotypes and alters common myeloid progenitor (CMP) differentiation by repressing the expression of mRNA splicing/processing genes, including SRSF2. RNA-seq analyses of telomere dysfunctional CMP identified aberrantly spliced transcripts linked to pathways relevant to MDS pathogenesis such as genome stability, DNA repair, chromatin remodeling, and histone modification, which are also enriched in mouse CMP haploinsufficient for SRSF2 and in CD34(+) CMML patient cells harboring SRSF2 mutation. Together, our studies establish an intimate link across telomere biology, aberrant RNA splicing, and myeloid progenitor differentiation.

Comment in

PMID:
25965571
PMCID:
PMC4596059
DOI:
10.1016/j.ccell.2015.04.007
[Indexed for MEDLINE]
Free PMC Article

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