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Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia

Nature Medicine volume 16, pages 903–908 (2010)Cite this article

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Abstract

RNA-binding proteins of the Musashi (Msi) family are expressed in stem cell compartments and in aggressive tumors, but they have not yet been widely explored in the blood. Here we demonstrate that Msi2 is the predominant form expressed in hematopoietic stem cells (HSCs), and its knockdown leads to reduced engraftment and depletion of HSCs in vivo. Overexpression of human MSI2 in a mouse model increases HSC cell cycle progression and cooperates with the chronic myeloid leukemia–associated BCR-ABL1 oncoprotein to induce an aggressive leukemia. MSI2 is overexpressed in human myeloid leukemia cell lines, and its depletion leads to decreased proliferation and increased apoptosis. Expression levels in human myeloid leukemia directly correlate with decreased survival in patients with the disease, thereby defining MSI2 expression as a new prognostic marker and as a new target for therapy in acute myeloid leukemia (AML).

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Figure 1: Msi2 is expressed in HSCs, and its depletion reduces engraftment in vivo.
Figure 2: Ectopic MSI2 expression compromises HSC function.
Figure 3: Ectopic MSI2 cooperates with BCR-ABL1 in promoting leukemia progression.
Figure 4: Increased MSI2 expression in human myeloid leukemias is associated with aggressive disease and immature phenotype.

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Acknowledgements

We would like to thank S. Armstrong (Children's Hospital Boston) for valuable reagents. We would like to acknowledge T. Zhang, D. Kalaitzidis, K. Gritsman, P. Stern and S. Sykes for their critical suggestions and J.-A. Kwon for assistance with microarray processing. We would like to thank M. Wernig for his assistance with the project. M.G.K. was supported by the US National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases Career Development Award. This work was supported by grants from the NIH (D.G.G., R.J. and G.Q.D.), the Leukemia and Lymphoma Society (D.G.G. and G.Q.D.) and the Howard Hughes Medical Institute (D.G.G. and G.Q.D.). C.J.L. was supported by a Ruth L. Kirschstein Fellowship from the NIH.

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Author notes

  1. Michael G Kharas and Christopher J Lengner: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Michael G Kharas, Fatima Al-Shahrour, Brian Ball, Kelly Morgan, Winnie Tam, Mahnaz Paktinat, Rachel Okabe, Maricel Gozo, William Einhorn, Benjamin L Ebert, D Gary Gilliland & George Q Daley

  2. Harvard Medical School, Boston, Massachusetts, USA

    Michael G Kharas, Benjamin L Ebert, D Gary Gilliland & George Q Daley

  3. Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA

    Christopher J Lengner & Rudolf Jaenisch

  4. Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA

    Fatima Al-Shahrour

  5. Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany

    Lars Bullinger, Claudia Scholl & Stefan Fröhling

  6. Department of Biology, Massachusetts Institute for Technology, Cambridge, Massachusetts, USA

    Samir Zaidi & Rudolf Jaenisch

  7. Division of Pediatric Hematology/Oncology, Children's Hospital, Boston, Massachusetts, USA

    William Einhorn, Steven W Lane & George Q Daley

  8. Department of Pathology, Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Mark Fleming

  9. Merck Research Laboratories, North Wales, Pennsylvania, USA

    D Gary Gilliland

  10. Howard Hughes Medical Institute, Boston, Massachusetts, USA

    George Q Daley

  11. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA

    George Q Daley

  12. Stem Cell Transplantation Program, Children's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    George Q Daley

  13. Harvard Stem Cell Institute, Cambridge, Massachusetts, USA

    George Q Daley

  14. Manton Center for Orphan Disease Research, Children's Hospital, Boston, Massachusetts, USA

    George Q Daley

Authors
  1. Michael G Kharas
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  2. Christopher J Lengner
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  3. Fatima Al-Shahrour
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  4. Lars Bullinger
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Contributions

M.G.K. led the project, performed the experiments and wrote the manuscript; C.J.L. performed experiments and revised the manuscript; F.A.-S. performed data analysis; L.B. provided clinical samples and microarray analysis; B.B., S.Z., K.M., W.T., M.P., R.O., M.G., W.E., C.S. and S.F. performed experiments; S.W.L. and M.F. provided pathology analysis; B.L.E. provided suggestions and project oversight; D.G.G., R.J. and G.Q.D. co-directed the project and revised the manuscript.

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Supplementary Figs. 1–16, Supplementary Tables 1–5 and Supplementary Methods (PDF 3164 kb)

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Kharas, M., Lengner, C., Al-Shahrour, F. et al. Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia. Nat Med 16, 903–908 (2010). https://doi.org/10.1038/nm.2187

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