Telomere Dysfunction Drives Aberrant Hematopoietic Differentiation and Myelodysplastic Syndrome

被引：76

作者：

Colla, Simona ^{[1
]}

Ong, Derrick Sek Tong ^{[2
]}

Ogoti, Yamini ^{[1
]}

Marchesini, Matteo ^{[1
]}

Mistry, Nipun A. ^{[3
]}

Clise-Dwyer, Karen ^{[4
]}

Ang, Sonny A. ^{[5
]}

Storti, Paola ^{[2
,6
]}

Viale, Andrea ^{[2
]}

Giuliani, Nicola ^{[6
]}

Ruisaard, Kathryn ^{[4
]}

Gomez, Irene Ganan ^{[1
]}

Bristow, Christopher A. ^{[7
]}

Estecio, Marcos ^{[1
,8
]}

Weksberg, David C. ^{[2
]}

Ho, Yan Wing ^{[2
]}

Hu, Baoli ^{[2
]}

Genovese, Giannicola ^{[2
]}

Pettazzoni, Piergiorgio ^{[2
]}

Multani, Asha S. ^{[9
]}

Jiang, Shan ^{[2
]}

Hua, Sujun ^{[2
]}

Ryan, Michael C. ^{[10
]}

Carugo, Alessandro ^{[2
]}

Nezi, Luigi ^{[2
]}

Wei, Yue ^{[1
]}

Yang, Hui ^{[1
]}

D'Anca, Marianna ^{[1
]}

Zhang, Li ^{[3
]}

Gaddis, Sarah ^{[8
]}

Gong, Ting ^{[8
]}

Horner, James W. ^{[7
]}

Heffernan, Timothy P. ^{[7
]}

Jones, Philip ^{[7
]}

Cooper, Laurence J. N. ^{[5
]}

Liang, Han ^{[3
]}

Kantarjian, Hagop ^{[1
]}

Wang, Y. Alan ^{[2
]}

Chin, Lynda ^{[2
]}

Bueso-Ramos, Carlos ^{[11
]}

Garcia-Manero, Guillermo ^{[1
]}

DePinho, Ronald A. ^{[12
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Stem Cell Transplantat & Cellular Therapy, Houston, TX 77030 USA

[5] Univ Texas MD Anderson Canc Ctr, Dept Pediat Res, Houston, TX 77030 USA

[6] Univ Parma, Dept Clin & Expt Med, Hematol, I-43126 Parma, Italy

[7] Univ Texas MD Anderson Canc Ctr, Inst Appl Canc Sci, Houston, TX 77030 USA

[8] Univ Texas MD Anderson Canc Ctr, Dept Mol Carcinogenesis, Smithville, TX 78957 USA

[9] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA

[10] In Sil Solut, Falls Church, VA 22043 USA

[11] Univ Texas MD Anderson Canc Ctr, Dept Hematopathol, Houston, TX 77030 USA

[12] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA

来源：

CANCER CELL | 2015年 / 27卷 / 05期

关键词：

ACUTE MYELOID-LEUKEMIA; STEM-CELLS; MUTATIONS; P53; PROGENITOR; EXPRESSION; COHESIN; STRESS;

D O I：

10.1016/j.ccell.2015.04.007

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：644 / 657

页数：14

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