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.
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: scolla@mdanderson.org.
authors.forename: Simona
authors.initials: S
authors.lastname: Colla
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Derrick Sek Tong
authors.initials: DS
authors.lastname: Ong
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yamini
authors.initials: Y
authors.lastname: Ogoti
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Matteo
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authors.lastname: Marchesini
authors.affiliation: Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Nipun A
authors.initials: NA
authors.lastname: Mistry
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Karen
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authors.lastname: Clise-Dwyer
authors.affiliation: Department of Pediatric Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Sonny A
authors.initials: SA
authors.lastname: Ang
authors.affiliation: 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.
authors.forename: Paola
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authors.lastname: Storti
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Viale
authors.affiliation: Hematology, Department of Clinical and Experimental Medicine, University of Parma, 43126 Parma, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Giuliani
authors.affiliation: Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Ruisaard
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Ganan Gomez
authors.affiliation: Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Bristow
authors.affiliation: 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.
authors.forename: Marcos
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authors.lastname: Estecio
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Weksberg
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yan Wing
authors.initials: YW
authors.lastname: Ho
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Baoli
authors.initials: B
authors.lastname: Hu
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Giannicola
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authors.lastname: Genovese
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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authors.lastname: Pettazzoni
authors.affiliation: Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Asha S
authors.initials: AS
authors.lastname: Multani
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Shan
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authors.lastname: Jiang
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Sujun
authors.initials: S
authors.lastname: Hua
authors.affiliation: In Silico Solutions, Falls Church, VA 22043, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Ryan
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Alessandro
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authors.lastname: Carugo
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Luigi
authors.initials: L
authors.lastname: Nezi
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Marianna
authors.initials: M
authors.lastname: D'Anca
authors.affiliation: Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Gaddis
authors.affiliation: Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Gong
authors.affiliation: Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: James W
authors.initials: JW
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authors.affiliation: Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Heffernan
authors.affiliation: Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Philip
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authors.lastname: Jones
authors.affiliation: Department of Pediatric Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Laurence J N
authors.initials: LJ
authors.lastname: Cooper
authors.affiliation: Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Liang
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hagop
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authors.lastname: Kantarjian
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Y Alan
authors.initials: YA
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authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Lynda
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authors.lastname: Chin
authors.affiliation: Department of Hematopathology, University of Texas MD Cancer Center, Houston, TX 77030, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Bueso-Ramos
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.affiliation: Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: rdepinho@mdanderson.org.
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D057895:Haploinsufficiency; D006410:Hematopoiesis / Q000235:genetics*; D006801:Humans; D051379:Mice; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D012326:RNA Splicing; D012261:Ribonucleoproteins / Q000235:genetics; D000068103:Serine-Arginine Splicing Factors; D016615:Telomere
chemical_list: D009687:Nuclear Proteins; D012261:Ribonucleoproteins; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors