title: MSI2 is required for maintaining activated myelodysplastic syndrome stem cells.
abstract: Myelodysplastic syndromes (MDS) are driven by complex genetic and epigenetic alterations. The MSI2 RNA-binding protein has been demonstrated to have a role in acute myeloid leukaemia and stem cell function, but its role in MDS is unknown. Here, we demonstrate that elevated MSI2 expression correlates with poor survival in MDS. Conditional deletion of Msi2 in a mouse model of MDS results in a rapid loss of MDS haematopoietic stem and progenitor cells (HSPCs) and reverses the clinical features of MDS. Inversely, inducible overexpression of MSI2 drives myeloid disease progression. The MDS HSPCs remain dependent on MSI2 expression after disease initiation. Furthermore, MSI2 expression expands and maintains a more activated (G1) MDS HSPC. Gene expression profiling of HSPCs from the MSI2 MDS mice identifies a signature that correlates with poor survival in MDS patients. Overall, we identify a role for MSI2 in MDS representing a therapeutic target in this disease.
authors.affiliation: Molecular Pharmacology and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: James
authors.initials: J
authors.lastname: Taggart
authors.affiliation: Molecular Pharmacology and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Tzu-Chieh
authors.initials: TC
authors.lastname: Ho
authors.affiliation: Molecular Pharmacology and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Elianna
authors.initials: E
authors.lastname: Amin
authors.affiliation: Memorial Sloan Kettering Cancer Center, Cancer Biology Program, New York, New York 10065, USA.
authors.forename: Haiming
authors.initials: H
authors.lastname: Xu
authors.affiliation: Molecular Pharmacology and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Trevor S
authors.initials: TS
authors.lastname: Barlowe
authors.affiliation: Computational Biology Program Memorial Sloan Kettering Cancer Center, Memorial Sloan Kettering Institute, New York, New York 10065, USA.
authors.forename: Alexendar R
authors.initials: AR
authors.lastname: Perez
authors.affiliation: Memorial Sloan Kettering Cancer Center, Human Oncology and Pathogenesis Program, New York, New York 10065, USA.
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Durham
authors.affiliation: Molecular Pharmacology and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Tivnan
authors.affiliation: Molecular Pharmacology and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Okabe
authors.affiliation: Molecular Pharmacology and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Chow
authors.affiliation: Molecular Pharmacology and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Ly
authors.initials: L
authors.lastname: Vu
authors.affiliation: Molecular Pharmacology and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Sun Mi
authors.initials: SM
authors.lastname: Park
authors.affiliation: Molecular Pharmacology and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Camila
authors.initials: C
authors.lastname: Prieto
authors.affiliation: Memorial Sloan Kettering Cancer Center, Department of Medicine, Leukemia Service, New York, New York 10065, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Famulare
authors.affiliation: Memorial Sloan Kettering Cancer Center, Department of Medicine, Leukemia Service, New York, New York 10065, USA.
authors.forename: Minal
authors.initials: M
authors.lastname: Patel
authors.affiliation: Department of Animal Biology, Department of Cell and Developmental Biology and Institute for Regenerative Medicine, Schools of Veterinary Medicine and Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lengner
authors.affiliation: Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Verma
authors.affiliation: Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: Gail
authors.initials: G
authors.lastname: Roboz
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine and Pharmacology, Weill Cornell Medical College, Cornell University, New York, New York 10065, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Guzman
authors.affiliation: Memorial Sloan Kettering Cancer Center, Department of Medicine, Leukemia Service, New York, New York 10065, USA.
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Klimek
authors.affiliation: Memorial Sloan Kettering Cancer Center, Human Oncology and Pathogenesis Program, New York, New York 10065, USA.
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.affiliation: Computational Biology Program Memorial Sloan Kettering Cancer Center, Memorial Sloan Kettering Institute, New York, New York 10065, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Leslie
authors.affiliation: Sylvester Comprehensive Cancer Center, Department of Medicine, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Nimer
authors.affiliation: Molecular Pharmacology and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Michael G
authors.identifier: http://orcid.org/0000-0002-1165-6991
authors.initials: MG
authors.lastname: Kharas
mesh_terms: D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D004195:Disease Models, Animal; D005260:Female; D006412:Hematopoietic Stem Cells / Q000502:physiology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009190:Myelodysplastic Syndromes / Q000209:etiology / Q000378:metabolism* / Q000401:mortality; D016601:RNA-Binding Proteins / Q000378:metabolism*
chemical_list: C438151:MSI2 protein, human; C499059:Msi2h protein, mouse; D016601:RNA-Binding Proteins