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; Michael G. Kharas

doi:10.1038/ncomms10739

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. KlimekOmar Abdel-Wahab, Christina Leslie, Stephen D. Nimer, Michael G. Kharas

Oncology

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

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 language	English (US)
Article number	10739
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms10739
State	Published - Feb 22 2016

ASJC Scopus subject areas

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

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10.1038/ncomms10739

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Taggart, J., Ho, T. C., Amin, E., Xu, H., Barlowe, T. S., Perez, A. R., Durham, B. H., Tivnan, P., Okabe, R., Chow, A., Vu, L., Park, S. M., Prieto, C., Famulare, C., Patel, M., Lengner, C. J., Verma, A., Roboz, G., Guzman, M., ... Kharas, M. G. (2016). MSI2 is required for maintaining activated myelodysplastic syndrome stem cells. Nature communications, 7, [10739]. https://doi.org/10.1038/ncomms10739

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, A, 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

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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.",

author = "James Taggart and Ho, {Tzu Chieh} and Elianna Amin and Haiming Xu and Barlowe, {Trevor S.} and Perez, {Alexendar R.} and Durham, {Benjamin H.} and Patrick Tivnan and Rachel Okabe and Arthur Chow and Ly Vu and Park, {Sun Mi} and Camila Prieto and Christopher Famulare and Minal Patel and Lengner, {Christopher J.} and Amit Verma and Gail Roboz and Monica Guzman and Klimek, {Virginia M.} and Omar Abdel-Wahab and Christina Leslie and Nimer, {Stephen D.} and Kharas, {Michael G.}",

note = "Funding Information: We would like to thank Ross Levine for helpful discussions. We would like to thank Aaron Chang for experimental support. We would also like to thank Aly Azeem Khan, Agnes Viale and the MSKCC sequencing core for all their support. M.G.K. is supported by the US National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; R01DK101989-01A1, National Cancer Institute R01, 1R01CA193842-01, MSK Cancer Center Support Grant/Core Grant (P30 CA008748), Louis V Gerstner Young Investigator Award, Kimmel Scholar Award and V-Scholar Award, Leukemia Research Foundation, C.J.L. was supported by an R01 from the National Cancer Institute (NIH), and a fellowship from the W.W. Smith Charitable Trust.",

year = "2016",

month = feb,

day = "22",

doi = "10.1038/ncomms10739",

language = "English (US)",

volume = "7",

journal = "Nature Communications",

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T1 - MSI2 is required for maintaining activated myelodysplastic syndrome stem cells

AU - Taggart, James

AU - Ho, Tzu Chieh

AU - Amin, Elianna

AU - Xu, Haiming

AU - Barlowe, Trevor S.

AU - Perez, Alexendar R.

AU - Durham, Benjamin H.

AU - Tivnan, Patrick

AU - Okabe, Rachel

AU - Chow, Arthur

AU - Vu, Ly

AU - Park, Sun Mi

AU - Prieto, Camila

AU - Famulare, Christopher

AU - Patel, Minal

AU - Lengner, Christopher J.

AU - Verma, Amit

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.

N1 - Funding Information: We would like to thank Ross Levine for helpful discussions. We would like to thank Aaron Chang for experimental support. We would also like to thank Aly Azeem Khan, Agnes Viale and the MSKCC sequencing core for all their support. M.G.K. is supported by the US National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; R01DK101989-01A1, National Cancer Institute R01, 1R01CA193842-01, MSK Cancer Center Support Grant/Core Grant (P30 CA008748), Louis V Gerstner Young Investigator Award, Kimmel Scholar Award and V-Scholar Award, Leukemia Research Foundation, C.J.L. was supported by an R01 from the National Cancer Institute (NIH), and a fellowship from the W.W. Smith Charitable Trust.

PY - 2016/2/22

Y1 - 2016/2/22

N2 - 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.

AB - 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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VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 10739

ER -

MSI2 is required for maintaining activated myelodysplastic syndrome stem cells

Abstract

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