Telomere Dysfunction Drives Aberrant Hematopoietic Differentiation and Myelodysplastic Syndrome
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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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Late-generation telomerase-deficient mice recapitulate myelodysplastic features that can be reversed by telomerase reactivation.
“Moreover, late-generation telomerase-deficient mice recapitulate myelodysplastic features that can be reversed by telomerase reactivation91.”
From Telomere dysfunction in ageing and age-related diseases (2022) · cites this paper as [91]
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Cites
Differential expression analysis for sequence count data
Anders, S., & Huber, W. (2010) · Genome Biology · doi:10.1186/gb-2010-11-10-r106 · Cited by 15,581 · see citing works
Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia
The Cancer Genome Atlas Research Network (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1301689 · Cited by 5,078 · see citing works
A DNA damage checkpoint response in telomere-initiated senescence
Fagagna, F. D. D., Reaper, P. M., Clay-Farrace, L., Fiegler, H., Carr, P., von Zglinicki, T., Saretzki, G., Carter, N. P., & Jackson, S. P. (2003) · Nature · doi:10.1038/nature02118 · Cited by 2,855 · cited 1× · see citing works
“…of age-associated DNA damage signaling can derive from progressive telomere erosion and damage which appears to provide a reservoir of persistent DNA damage signaling in the context of aging cells (Chin et al., 1999; d’Adda di Fagagna et al., 2003; Karlseder et al., 2002; Rudolph et al., 1999).”
BackgroundCell-cycle checkpoints and cancer
Kastan, M. B., & Bartek, J. (2004) · Nature · doi:10.1038/nature03097 · Cited by 2,836 · see citing works
A clonogenic common myeloid progenitor that gives rise to all myeloid lineages
Akashi, K., Traver, D., Miyamoto, T., & Weissman, I. L. (2000) · Nature · doi:10.1038/35004599 · Cited by 2,617 · see citing works
Frequent pathway mutations of splicing machinery in myelodysplasia
Yoshida, K., Sanada, M., Shiraishi, Y., Nowak, D., Nagata, Y., Yamamoto, R., Sato, Y., Sato-Otsubo, A., Kon, A., Nagasaki, M., et al. (2011) · Nature · doi:10.1038/nature10496 · Cited by 2,029 · see citing works
Clinical Effect of Point Mutations in Myelodysplastic Syndromes
Bejar, R., Stevenson, K., Abdel-Wahab, O., Galili, N., Nilsson, B., Garcia-Manero, G., Kantarjian, H., Raza, A., Levine, R. L., Neuberg, D., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1013343 · Cited by 1,627 · see citing works
Self-citationDetecting differential usage of exons from RNA-seq data
Anders, S., Reyes, A., & Huber, W. (2012) · Genome Research · doi:10.1101/gr.133744.111 · Cited by 1,545 · see citing works
Longevity, Stress Response, and Cancer in Aging Telomerase-Deficient Mice
Rudolph, K. L., Chang, S., Lee, H.-W., Blasco, M., Gottlieb, G. J., Greider, C., & DePinho, R. A. (1999) · Cell · doi:10.1016/s0092-8674(00)80580-2 · Cited by 1,349 · cited 3× · see citing works
“These processes are particularly evident in tissues with high cell turnover rate, including the hematopoietic system (Lee et al., 1998; Rudolph et al., 1999).”
BackgroundSelf-citationEssential role of mouse telomerase in highly proliferative organs
Lee, H.-W., Blasco, M. A., Gottlieb, G. J., Horner, J. W., Greider, C. W., & DePinho, R. A. (1998) · Nature · doi:10.1038/33345 · Cited by 1,270 · cited 5× · see citing works
“Of relevance to this study, it is worth noting that the specific type of cellular response (e.g., apoptosis, cell cycle, etc.) in telomere dysfunctional mice can vary depending on cell type (Lee et al., 1998).”
BackgroundInfluentialSelf-citationDnmt3a is essential for hematopoietic stem cell differentiation
Challen, G. A., Sun, D., Jeong, M., Luo, M., Jelinek, J., Berg, J. S., Bock, C., Vasanthakumar, A., Gu, H., Xi, Y., et al. (2012) · Nature Genetics · doi:10.1038/ng.1009 · Cited by 1,122 · see citing works
Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age
Rossi, D. J., Bryder, D., Seita, J., Nussenzweig, A., Hoeijmakers, J., & Weissman, I. L. (2007) · Nature · doi:10.1038/nature05862 · Cited by 1,115 · see citing works
Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome
Lang, G. A., Iwakuma, T., Suh, Y.-A., Liu, G., Rao, V. A., Parant, J. M., Valentin-Vega, Y. A., Terzian, T., Caldwell, L. C., Strong, L. C., et al. (2004) · Cell · doi:10.1016/j.cell.2004.11.006 · Cited by 1,069 · see citing works
Chin, L., Artandi, S. E., Shen, Q., Tam, A., Lee, S.-L., Gottlieb, G. J., Greider, C. W., & DePinho, R. A. (1999) · Cell · doi:10.1016/s0092-8674(00)80762-x · Cited by 979 · cited 2× · see citing works
“A source of age-associated DNA damage signaling can derive from progressive telomere erosion and damage which appears to provide a reservoir of persistent DNA damage signaling in the context of aging cells (Chin et al., 1999; d’Adda di Fagagna et al., 2003; Karlseder et al., 2002; Rudolph et al., 1999).”
Self-citationTelomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice
Jaskelioff, M., Muller, F. L., Paik, J.-H., Thomas, E., Jiang, S., Adams, A. C., Sahin, E., Kost-Alimova, M., Protopopov, A., Cadiñanos, J., et al. (2011) · Nature · doi:10.1038/nature09603 · Cited by 857 · cited 8× · see citing works
“In the late generation G4/G5 TERTER/ER mice, systemic administration of OHT restores telomeres, quells DNA damage signaling, and reverses tissue degeneration phenotypes (Jaskelioff et al., 2011).”
BackgroundMethodInfluentialSelf-citationSenescence Induced by Altered Telomere State, Not Telomere Loss
Karlseder, J., Smogorzewska, A., & de Lange, T. (2002) · Science · doi:10.1126/science.1069523 · Cited by 796 · see citing works
Yamamoto, R., Morita, Y., Ooehara, J., Hamanaka, S., Onodera, M., Rudolph, K. L., Ema, H., & Nakauchi, H. (2013) · Cell · doi:10.1016/j.cell.2013.08.007 · Cited by 745 · see citing works
Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia.
Goardon, N., Marchi, E., Atzberger, A., Quek, L., Schuh, A., Soneji, S., Woll, P., Mead, A., Alford, K., Rout, R., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2010.12.012 · Cited by 671 · see citing works
Rollison, D. E. M., Howlader, N., Smith, M. T., Strom, S. S., Merritt, W. D., Ries, L. A. G., Edwards, B. K., & List, A. F. (2008) · Blood · doi:10.1182/blood-2008-01-134858 · Cited by 663 · see citing works
Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells
Flach, J., Bakker, S. T., Mohrin, M., Conroy, P. C., Pietras, E. M., Reynaud, D., Alvarez, S., Diolaiti, M. E., Ugarte, F., Forsberg, E. C., et al. (2014) · Nature · doi:10.1038/nature13619 · Cited by 650 · see citing works
Splicing factor SF3b as a target of the antitumor natural product pladienolide
Kotake, Y., Sagane, K., Owa, T., Mimori‐Kiyosue, Y., Shimizu, H., Uesugi, M., Ishihama, Y., Iwata, M., & Mizui, Y. (2007) · Nature Chemical Biology · doi:10.1038/nchembio.2007.16 · Cited by 648 · see citing works
Regulation of Alternative Splicing in Vivo by Overexpression of Antagonistic Splicing Factors
Cáceres, J. F., Stamm, S., Helfman, D. M., & Krainer, A. R. (1994) · Science · doi:10.1126/science.8085156 · Cited by 619 · see citing works
Recurrent DNMT3A mutations in patients with myelodysplastic syndromes
Walter, M. J., Ding, L., Shen, D., Shao, J., Grillot, M., McLellan, M., Fulton, R., Schmidt, H., Kalicki-Veizer, J., O'Laughlin, M., et al. (2011) · Leukemia · doi:10.1038/leu.2011.44 · Cited by 527 · see citing works
Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells
Nakada, D., Saunders, T. L., & Morrison, S. J. (2010) · Nature · doi:10.1038/nature09571 · Cited by 524 · see citing works
Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms
Kon, A., Shih, L., Minamino, M., Sanada, M., Shiraishi, Y., Nagata, Y., Yoshida, K., Okuno, Y., Bando, M., Nakato, R., et al. (2013) · Nature Genetics · doi:10.1038/ng.2731 · Cited by 384 · see citing works
Axis of ageing: telomeres, p53 and mitochondria
Sahin, E., & DePinho, R. A. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3352 · Cited by 380 · see citing works
Self-citationA Differentiation Checkpoint Limits Hematopoietic Stem Cell Self-Renewal in Response to DNA Damage
Wang, J., Sun, Q., Morita, Y., Jiang, H., Groß, A., Lechel, A., Hildner, K., Guachalla, L. M., Gompf, A., Hartmann, D., et al. (2012) · Cell · doi:10.1016/j.cell.2012.01.040 · Cited by 343 · see citing works
Allsopp, R. C., Morin, G. B., DePinho, R., Harley, C. B., & Weissman, I. L. (2003) · Blood · doi:10.1182/blood-2002-07-2334 · Cited by 324 · see citing works
Self-citationMisregulation of Pre-mRNA Alternative Splicing in Cancer
Zhang, J., & Manley, J. L. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0253 · Cited by 306 · see citing works
Ju, Z., Jiang, H., Jaworski, M., Rathinam, C., Gompf, A., Klein, C., Trumpp, A., & Rudolph, K. L. (2007) · Nature Medicine · doi:10.1038/nm1578 · Cited by 284 · see citing works
Milyavsky, M., Gan, O. I., Trottier, M., Komosa, M., Tabach, O., Notta, F., Lechman, E. R., Hermans, K. G., Eppert, K., Konovalova, Z., et al. (2010) · Cell stem cell · doi:10.1016/j.stem.2010.05.016 · Cited by 280 · see citing works
Hematopoietic stem cell and progenitor cell mechanisms in myelodysplastic syndromes
Pang, W. W., Pluvinage, J. V., Price, E. A., Sridhar, K., Arber, D. A., Greenberg, P. L., Schrier, S. L., Park, C. Y., & Weissman, I. L. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1222861110 · Cited by 277 · see citing works
Clonal architecture of chronic myelomonocytic leukemias
Itzykson, R., Kosmider, O., Renneville, A., Morabito, M., Preudhomme, C., Berthon, C., Adès, L., Fenaux, P., Platzbecker, U., Gagey, O., et al. (2013) · Blood · doi:10.1182/blood-2012-06-440347 · Cited by 276 · see citing works
Dnmt3a loss predisposes murine hematopoietic stem cells to malignant transformation
Mayle, A., Yang, L., Rodriguez, B., Zhou, T., Chang, E., Curry, C. V., Challen, G. A., Li, W., Wheeler, D., Rebel, V. I., et al. (2015) · Blood · doi:10.1182/blood-2014-08-594648 · Cited by 235 · see citing works
Will, B., Zhou, L., Vogler, T. O., Ben-Neriah, S., Schinke, C., Tamari, R., Yu, Y., Bhagat, T., Bhattacharyya, S., Barreyro, L., et al. (2012) · Blood · doi:10.1182/blood-2011-12-399683 · Cited by 223 · see citing works
SR Proteins and Related Factors in Alternative Splicing
Lin, S., & Fu, X. (2007) · Advances in experimental medicine and biology · doi:10.1007/978-0-387-77374-2_7 · Cited by 213 · see citing works
Familial myelodysplasia and acute myeloid leukaemia – a review
Owen, C., Barnett, M. J., & Fitzgibbon, J. (2007) · British Journal of Haematology · doi:10.1111/j.1365-2141.2007.06909.x · Cited by 186 · see citing works
The Ancient and Evolving Roles of Cohesin in Gene Expression and DNA Repair
Dorsett, D., & Ström, L. (2012) · Current Biology · doi:10.1016/j.cub.2012.02.046 · Cited by 141 · see citing works
DNA damage in stem cells activates p21, inhibits p53, and induces symmetric self-renewing divisions.
Insinga, A., Cicalese, A., Faretta, M., Gallo, B., Albano, L., Ronzoni, S., Furia, L., Viale, A., & Pelicci, P. G. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1213394110 · Cited by 140 · see citing works
Self-citationPRPF8 defects cause missplicing in myeloid malignancies
Kurtović-Kozarić, A., Przychodzen, B. P., Singh, J., Konarska, M. M., Clemente, M. J., Otrock, Z. K., Nakashima, M. O., Hsi, E. D., Yoshida, K., Shiraishi, Y., et al. (2014) · Leukemia · doi:10.1038/leu.2014.144 · Cited by 121 · see citing works
The myelodysplastic syndrome as a prototypical epigenetic disease
Issa, J. J. (2013) · Blood · doi:10.1182/blood-2013-02-451757 · Cited by 100 · see citing works
The Changing Mutational Landscape of Acute Myeloid Leukemia and Myelodysplastic Syndrome
Larsson, C. A., Cote, G. J., & Quintás‐Cardama, A. (2013) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-12-0695 · Cited by 94 · see citing works
Berg, M. G., Wan, L., Younis, I., Diem, M. D., Soo, M., Wang, C., & Dreyfuss, G. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.05788-11 · Cited by 40 · see citing works
Myelodysplastic syndrome: An inability to appropriately respond to damaged DNA?
Zhou, T., Hasty, P., Walter, C. A., Bishop, A. J. R., Scott, L. M., & Rebel, V. I. (2013) · Experimental Hematology · doi:10.1016/j.exphem.2013.04.008 · Cited by 39 · cited 3× · see citing works
“MDS incidence has risen dramatically in recent years (Rollison et al., 2008) and is associated with advanced age, shorter telomeres, cancer chemotherapy with alkylating agents, radiation, and inherited syndromes related to abnormalities in DNA repair (Zhou et al., 2013).”
BackgroundThe Paf oncogene is essential for hematopoietic stem cell function and development
Amrani, Y. M., Gill, J. B., Matevossian, A., Alonzo, E. S., Yang, C., Shieh, J.-H., Moore, M. A. S., Park, C. Y., Sant’Angelo, D. B., & Denzin, L. K. (2011) · The Journal of Experimental Medicine · doi:10.1084/jem.20102170 · Cited by 27 · see citing works
Geiselhart, A., Lier, A., Walter, D., & Milsom, M. D. (2012) · Anemia · doi:10.1155/2012/265790 · Cited by 19 · see citing works
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Telomeres: history, health, and hallmarks of aging
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Florez, M. A., Tran, B. T., Wathan, T. K., DeGregori, J., Pietras, E. M., & King, K. Y. (2022) · Cell Stem Cell · doi:10.1016/j.stem.2022.05.006 · Cited by 129 · see citing works
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McNeely, T., Leone, M., Yanai, H., & Beerman, I. (2020) · Human Genetics · doi:10.1007/s00439-019-02047-z · Cited by 52 · see citing works
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- Authors
- 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., Multani, A. S., Jiang, S., Hua, S., Ryan, M. C., Carugo, A., Nezi, L., Wei, Y., Yang, H., D’Anca, M., Zhang, L., Gaddis, S., Gong, T., Horner, J. W., Heffernan, T. P., Jones, P., Cooper, L. J. N., Liang, H., Kantarjian, H., Wang, Y. A., Chin, L., Bueso-Ramos, C., Garcia-Manero, G., & DePinho, R. A.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- University of Parma (IT)
- Corresponding author
- Colla, Simona
- DePinho, Ronald A.
- ORCID
- Colla, Simona
- Ong, Derrick Sek Tong
- Marchesini, Matteo
- Clise-Dwyer, Karen
- Storti, Paola
- Viale, Andrea
- Giuliani, Nicola
- Bristow, Christopher A.
- Estecio, Marcos
- Hu, Baoli
- Genovese, Giannicola
- Pettazzoni, Piergiorgio
- Multani, Asha S.
- Jiang, Shan
- Carugo, Alessandro
- Nezi, Luigi
- Wei, Yue
- Yang, Hui
- D’Anca, Marianna
- Zhang, Li
- Gong, Ting
- Heffernan, Timothy P.
- Jones, Philip
- Cooper, Laurence J.N.
- Liang, Han
- Kantarjian, Hagop
- Wang, Y. Alan
- Bueso-Ramos, Carlos
- DePinho, Ronald A.
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2015-05
- Volume
- 27
- Issue
- 5
- Pages
- 644-657
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC4596059
- OpenAlex
- W1514913206
- Cited by
- 105
- References
- 46
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 5 · 2023: 9 · 2022: 11 · 2021: 7 · 2020: 8 · 2019: 8 · 2018: 12 · 2017: 15 · 2016: 14 · 2015: 7
- FWCI
- 11.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Laura and John Arnold Foundation
- National Institutes of Health
- University of Texas MD Anderson Cancer Center
- National Cancer Institute (P30CA16672, CA143883, U24CA143883, R01CA084628, P30CA016672)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- telomere dysfunction, myelodysplastic syndrome, aberrant splicing, SRSF2, DNA damage, telomere shortening, haploinsufficiency, chronic myelomonocytic leukemia, genome stability, DNA repair, chromatin remodeling, histone modifications
- MeSH terms
- Serine-Arginine Splicing Factors, Animals, Cell Differentiation, Hematopoiesis, Humans, Myelodysplastic Syndromes, Nuclear Proteins, Ribonucleoproteins, RNA Splicing, Telomere, Mice, Haploinsufficiency
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