Telomere Dysfunction Drives Aberrant Hematopoietic Differentiation and Myelodysplastic Syndrome

Simona Colla; Derrick Sek Tong Ong; Yamini Ogoti; Matteo Marchesini; Nipun A. Mistry; Karen Clise-Dwyer; Sonny A. Ang; Paola Storti; Andrea Viale; Nicola Giuliani; Kathryn Ruisaard; Irene Ganan Gomez; Christopher A. Bristow; Marcos Estecio; David C. Weksberg; Yan Wing Ho; Baoli Hu; Giannicola Genovese; Piergiorgio Pettazzoni; Asha S. Multani; Shan Jiang; Sujun Hua; Michael C. Ryan; Alessandro Carugo; Luigi Nezi; Yue Wei; Hui Yang; Marianna D'Anca; Li Zhang; Sarah Gaddis; Ting Gong; James W. Horner; Timothy P. Heffernan; Philip Jones; Laurence J.N. Cooper; Han Liang; Hagop Kantarjian; Y. Alan Wang; Lynda Chin; Carlos Bueso-Ramos; Guillermo Garcia-Manero; Ronald A. DePinho

doi:10.1016/j.ccell.2015.04.007

Telomere Dysfunction Drives Aberrant Hematopoietic Differentiation and Myelodysplastic Syndrome

Simona Colla, Derrick Sek Tong Ong, Yamini Ogoti, Matteo Marchesini, Nipun A. Mistry, Karen Clise-Dwyer, Sonny A. Ang, Paola Storti, Andrea Viale, Nicola Giuliani, Kathryn Ruisaard, Irene Ganan Gomez, Christopher A. Bristow, Marcos Estecio, David C. Weksberg, Yan Wing Ho, Baoli Hu, Giannicola Genovese, Piergiorgio Pettazzoni, Asha S. MultaniShan Jiang, Sujun Hua, Michael C. Ryan, Alessandro Carugo, Luigi Nezi, Yue Wei, Hui Yang, Marianna D'Anca, Li Zhang, Sarah Gaddis, Ting Gong, James W. Horner, Timothy P. Heffernan, Philip Jones, Laurence J.N. Cooper, Han Liang, Hagop Kantarjian, Y. Alan Wang, Lynda Chin, Carlos Bueso-Ramos, Guillermo Garcia-Manero, Ronald A. DePinho

Research output: Contribution to journal › Article › peer-review

81 Scopus citations

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.

Original language	English (US)
Pages (from-to)	644-657
Number of pages	14
Journal	Cancer cell
Volume	27
Issue number	5
DOIs	https://doi.org/10.1016/j.ccell.2015.04.007
State	Published - May 11 2015

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

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Colla, S., Ong, D. S. T., Ogoti, Y., Marchesini, M., Mistry, N. A., Clise-Dwyer, K., Ang, S. A., Storti, P., Viale, A., Giuliani, N., Ruisaard, K., Ganan Gomez, I., Bristow, C. A., Estecio, M., Weksberg, D. C., Ho, Y. W., Hu, B., Genovese, G., Pettazzoni, P., ... DePinho, R. A. (2015). Telomere Dysfunction Drives Aberrant Hematopoietic Differentiation and Myelodysplastic Syndrome. Cancer cell, 27(5), 644-657. https://doi.org/10.1016/j.ccell.2015.04.007

Colla, S, Ong, DST, Ogoti, Y, Marchesini, M, Mistry, NA, Clise-Dwyer, K , Ang, SA, Storti, P, Viale, A, Giuliani, N, Ruisaard, K, Ganan Gomez, I, Bristow, CA , Estecio, M, Weksberg, DC, Ho, YW, Hu, B, Genovese, G, Pettazzoni, P, Multani, AS, Jiang, S, Hua, S, Ryan, MC, Carugo, A, Nezi, L, Wei, Y , Yang, H, D'Anca, M, Zhang, L, Gaddis, S, Gong, T, Horner, JW, Heffernan, TP, Jones, P, Cooper, LJN, Liang, H , Kantarjian, H, Wang, YA, Chin, L, Bueso-Ramos, C , Garcia-Manero, G & DePinho, RA 2015, 'Telomere Dysfunction Drives Aberrant Hematopoietic Differentiation and Myelodysplastic Syndrome', Cancer cell, vol. 27, no. 5, pp. 644-657. https://doi.org/10.1016/j.ccell.2015.04.007

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title = "Telomere Dysfunction Drives Aberrant Hematopoietic Differentiation and Myelodysplastic Syndrome",

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.",

author = "Simona Colla and Ong, {Derrick Sek Tong} and Yamini Ogoti and Matteo Marchesini and Mistry, {Nipun A.} and Karen Clise-Dwyer and Ang, {Sonny A.} and Paola Storti and Andrea Viale and Nicola Giuliani and Kathryn Ruisaard and {Ganan Gomez}, Irene and Bristow, {Christopher A.} and Marcos Estecio and Weksberg, {David C.} and Ho, {Yan Wing} and Baoli Hu and Giannicola Genovese and Piergiorgio Pettazzoni and Multani, {Asha S.} and Shan Jiang and Sujun Hua and Ryan, {Michael C.} and Alessandro Carugo and Luigi Nezi and Yue Wei and Hui Yang and Marianna D'Anca and Li Zhang and Sarah Gaddis and Ting Gong and Horner, {James W.} and Heffernan, {Timothy P.} and Philip Jones and Cooper, {Laurence J.N.} and Han Liang and Hagop Kantarjian and Wang, {Y. Alan} and Lynda Chin and Carlos Bueso-Ramos and Guillermo Garcia-Manero and DePinho, {Ronald A.}",

note = "Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

month = may,

day = "11",

doi = "10.1016/j.ccell.2015.04.007",

language = "English (US)",

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T1 - Telomere Dysfunction Drives Aberrant Hematopoietic Differentiation and Myelodysplastic Syndrome

AU - Colla, Simona

AU - Ong, Derrick Sek Tong

AU - Ogoti, Yamini

AU - Marchesini, Matteo

AU - Mistry, Nipun A.

AU - Clise-Dwyer, Karen

AU - Ang, Sonny A.

AU - Storti, Paola

AU - Viale, Andrea

AU - Giuliani, Nicola

AU - Ruisaard, Kathryn

AU - Ganan Gomez, Irene

AU - Bristow, Christopher A.

AU - Estecio, Marcos

AU - Weksberg, David C.

AU - Ho, Yan Wing

AU - Hu, Baoli

AU - Genovese, Giannicola

AU - Pettazzoni, Piergiorgio

AU - Multani, Asha S.

AU - Jiang, Shan

AU - Hua, Sujun

AU - Ryan, Michael C.

AU - Carugo, Alessandro

AU - Nezi, Luigi

AU - Wei, Yue

AU - Yang, Hui

AU - D'Anca, Marianna

AU - Zhang, Li

AU - Gaddis, Sarah

AU - Gong, Ting

AU - Horner, James W.

AU - Heffernan, Timothy P.

AU - Jones, Philip

AU - Cooper, Laurence J.N.

AU - Liang, Han

AU - Kantarjian, Hagop

AU - Wang, Y. Alan

AU - Chin, Lynda

AU - Bueso-Ramos, Carlos

AU - Garcia-Manero, Guillermo

AU - DePinho, Ronald A.

PY - 2015/5/11

Y1 - 2015/5/11

N2 - 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.

AB - 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.

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SN - 1535-6108

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JO - Cancer cell

JF - Cancer cell

IS - 5

ER -

Telomere Dysfunction Drives Aberrant Hematopoietic Differentiation and Myelodysplastic Syndrome

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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