MSI2 is required for maintaining activated myelodysplastic syndrome stem cells

James Taggart, Tzu-Chieh Ho, Elianna Amin, Haiming Xu, Trevor S. Barlowe, Alexendar R. Perez, Benjamin H. Durham, Patrick Tivnan, Rachel Okabe, Arthur Chow, Ly Vu, Sun Mi Park, Camila Prieto, Christopher Famulare, Minal Patel, Christopher J. Lengner, Amit Verma, Gail Roboz, Monica Guzman, Virginia M. Klimek, Omar Abdel-Wahab, Christina Leslie, Stephen D. Nimer and Michael G. Kharas ()
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James Taggart: Molecular Pharmacology and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Memorial Sloan Kettering Cancer Center
Tzu-Chieh Ho: Molecular Pharmacology and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Memorial Sloan Kettering Cancer Center
Elianna Amin: Molecular Pharmacology and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Memorial Sloan Kettering Cancer Center
Haiming Xu: Memorial Sloan Kettering Cancer Center, Cancer Biology Program
Trevor S. Barlowe: Molecular Pharmacology and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Memorial Sloan Kettering Cancer Center
Alexendar R. Perez: Computational Biology Program Memorial Sloan Kettering Cancer Center, Memorial Sloan Kettering Institute
Benjamin H. Durham: Memorial Sloan Kettering Cancer Center, Human Oncology and Pathogenesis Program
Patrick Tivnan: Molecular Pharmacology and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Memorial Sloan Kettering Cancer Center
Rachel Okabe: Molecular Pharmacology and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Memorial Sloan Kettering Cancer Center
Arthur Chow: Molecular Pharmacology and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Memorial Sloan Kettering Cancer Center
Ly Vu: Molecular Pharmacology and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Memorial Sloan Kettering Cancer Center
Sun Mi Park: Molecular Pharmacology and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Memorial Sloan Kettering Cancer Center
Camila Prieto: Molecular Pharmacology and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Memorial Sloan Kettering Cancer Center
Christopher Famulare: Memorial Sloan Kettering Cancer Center, Leukemia Service
Minal Patel: Memorial Sloan Kettering Cancer Center, Leukemia Service
Christopher J. Lengner: Schools of Veterinary Medicine and Medicine, University of Pennsylvania
Amit Verma: Montefiore Medical Center, Albert Einstein College of Medicine
Gail Roboz: Weill Cornell Medical College
Monica Guzman: Weill Cornell Medical College, Cornell University
Virginia M. Klimek: Memorial Sloan Kettering Cancer Center, Leukemia Service
Omar Abdel-Wahab: Memorial Sloan Kettering Cancer Center, Human Oncology and Pathogenesis Program
Christina Leslie: Computational Biology Program Memorial Sloan Kettering Cancer Center, Memorial Sloan Kettering Institute
Stephen D. Nimer: Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA
Michael G. Kharas: Molecular Pharmacology and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Memorial Sloan Kettering Cancer Center

Nature Communications, 2016, vol. 7, issue 1, 1-8

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10739

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