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 K. Verma, Gail Roboz, Monica Guzman, Virginia M. Klimek & 4 others Omar Abdel-Wahab, Christina Leslie, Stephen D. Nimer, Michael G. Kharas

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Article number10739
JournalNature Communications
Volume7
DOIs
StatePublished - Feb 22 2016

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stem cells
Myelodysplastic Syndromes
Stem cells
Stem Cells
Hematopoietic Stem Cells
RNA-Binding Proteins
Gene expression
stems
cells
mice
Myeloid Progenitor Cells
deletion
leukemias
Survival
gene expression
Gene Expression Profiling
Acute Myeloid Leukemia
Epigenomics
progressions
Disease Progression

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Taggart, J., Ho, T. C., Amin, E., Xu, H., Barlowe, T. S., Perez, A. R., ... Kharas, M. G. (2016). MSI2 is required for maintaining activated myelodysplastic syndrome stem cells. Nature Communications, 7, [10739]. https://doi.org/10.1038/ncomms10739

MSI2 is required for maintaining activated myelodysplastic syndrome stem cells. / Taggart, James; Ho, Tzu Chieh; Amin, Elianna; Xu, Haiming; Barlowe, Trevor S.; Perez, Alexendar R.; Durham, Benjamin H.; Tivnan, Patrick; Okabe, Rachel; Chow, Arthur; Vu, Ly; Park, Sun Mi; Prieto, Camila; Famulare, Christopher; Patel, Minal; Lengner, Christopher J.; Verma, Amit K.; Roboz, Gail; Guzman, Monica; Klimek, Virginia M.; Abdel-Wahab, Omar; Leslie, Christina; Nimer, Stephen D.; Kharas, Michael G.

In: Nature Communications, Vol. 7, 10739, 22.02.2016.

Research output: Contribution to journalArticle

Taggart, J, Ho, TC, Amin, E, Xu, H, Barlowe, TS, Perez, AR, Durham, BH, Tivnan, P, Okabe, R, Chow, A, Vu, L, Park, SM, Prieto, C, Famulare, C, Patel, M, Lengner, CJ, Verma, AK, Roboz, G, Guzman, M, Klimek, VM, Abdel-Wahab, O, Leslie, C, Nimer, SD & Kharas, MG 2016, 'MSI2 is required for maintaining activated myelodysplastic syndrome stem cells', Nature Communications, vol. 7, 10739. https://doi.org/10.1038/ncomms10739
Taggart, James ; Ho, Tzu Chieh ; Amin, Elianna ; Xu, Haiming ; Barlowe, Trevor S. ; Perez, Alexendar R. ; Durham, Benjamin H. ; Tivnan, Patrick ; Okabe, Rachel ; Chow, Arthur ; Vu, Ly ; Park, Sun Mi ; Prieto, Camila ; Famulare, Christopher ; Patel, Minal ; Lengner, Christopher J. ; Verma, Amit K. ; Roboz, Gail ; Guzman, Monica ; Klimek, Virginia M. ; Abdel-Wahab, Omar ; Leslie, Christina ; Nimer, Stephen D. ; Kharas, Michael G. / MSI2 is required for maintaining activated myelodysplastic syndrome stem cells. In: Nature Communications. 2016 ; Vol. 7.
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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.",
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AU - Perez, Alexendar R.

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AU - Roboz, Gail

AU - Guzman, Monica

AU - Klimek, Virginia M.

AU - Abdel-Wahab, Omar

AU - Leslie, Christina

AU - Nimer, Stephen D.

AU - Kharas, Michael G.

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