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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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References

  1. Sakakibara, S. et al. RNA-binding protein Musashi family: roles for CNS stem cells and a subpopulation of ependymal cells revealed by targeted disruption and antisense ablation. Proc. Natl. Acad. Sci. USA 99, 15194–15199 (2002).

    Article  CAS  Google Scholar 

  2. Wang, X.Y. et al. Musashi1 modulates mammary progenitor cell expansion through proliferin-mediated activation of the Wnt and Notch pathways. Mol. Cell. Biol. 28, 3589–3599 (2008).

    Article  CAS  Google Scholar 

  3. Tenen, D.G. Disruption of differentiation in human cancer: AML shows the way. Nat. Rev. Cancer 3, 89–101 (2003).

    Article  CAS  Google Scholar 

  4. Barbouti, A. et al. A novel gene, MSI2, encoding a putative RNA-binding protein is recurrently rearranged at disease progression of chronic myeloid leukemia and forms a fusion gene with HOXA9 as a result of the cryptic t(7;17)(p15;q23). Cancer Res. 63, 1202–1206 (2003).

    CAS  PubMed  Google Scholar 

  5. Hemmati, H.D. et al. Cancerous stem cells can arise from pediatric brain tumors. Proc. Natl. Acad. Sci. USA 100, 15178–15183 (2003).

    Article  CAS  Google Scholar 

  6. Wang, G.G., Pasillas, M.P. & Kamps, M.P. Persistent transactivation by meis1 replaces hox function in myeloid leukemogenesis models: evidence for co-occupancy of meis1-pbx and hox-pbx complexes on promoters of leukemia-associated genes. Mol. Cell. Biol. 26, 3902–3916 (2006).

    Article  CAS  Google Scholar 

  7. Okano, H. et al. Function of RNA-binding protein Musashi-1 in stem cells. Exp. Cell Res. 306, 349–356 (2005).

    Article  CAS  Google Scholar 

  8. Kawahara, H. et al. Neural RNA-binding protein Musashi1 inhibits translation initiation by competing with eIF4G for PABP. J. Cell Biol. 181, 639–653 (2008).

    Article  CAS  Google Scholar 

  9. Imai, T. et al. The neural RNA-binding protein Musashi1 translationally regulates mammalian numb gene expression by interacting with its mRNA. Mol. Cell. Biol. 21, 3888–3900 (2001).

    Article  CAS  Google Scholar 

  10. Kiel, M.J., Yilmaz, O.H., Iwashita, T., Terhorst, C. & Morrison, S.J. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121, 1109–1121 (2005).

    Article  CAS  Google Scholar 

  11. Hochedlinger, K., Yamada, Y., Beard, C. & Jaenisch, R. Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues. Cell 121, 465–477 (2005).

    Article  CAS  Google Scholar 

  12. Beard, C., Hochedlinger, K., Plath, K., Wutz, A. & Jaenisch, R. Efficient method to generate single-copy transgenic mice by site-specific integration in embryonic stem cells. Genesis 44, 23–28 (2006).

    Article  CAS  Google Scholar 

  13. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545–15550 (2005).

    Article  CAS  Google Scholar 

  14. Wu, M. et al. Imaging hematopoietic precursor division in real time. Cell Stem Cell 1, 541–554 (2007).

    Article  CAS  Google Scholar 

  15. Sureban, S.M. et al. Knockdown of RNA binding protein musashi-1 leads to tumor regression in vivo. Gastroenterology 134, 1448–1458 (2008).

    Article  CAS  Google Scholar 

  16. Huntly, B.J. et al. MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell 6, 587–596 (2004).

    Article  CAS  Google Scholar 

  17. Kanai, R. et al. Augmented therapeutic efficacy of an oncolytic herpes simplex virus type 1 mutant expressing ICP34.5 under the transcriptional control of musashi1 promoter in the treatment of malignant glioma. Hum. Gene Ther. 18, 63–73 (2007).

    Article  CAS  Google Scholar 

  18. Nikpour, P. et al. The RNA binding protein Musashi1 regulates apoptosis, gene expression and stress granule formation in urothelial carcinoma cells. J. Cell. Mol. Med. published online, doi:10.1111/j.1582-4934.2010.01090.x (14 May 2010).

  19. Kanai, R. et al. Enhanced therapeutic efficacy of oncolytic herpes vector G207 against human non-small cell lung cancer–expression of an RNA-binding protein, Musashi1, as a marker for the tailored gene therapy. J. Gene Med. 8, 1329–1340 (2006).

    Article  CAS  Google Scholar 

  20. Creighton, C.J. Multiple oncogenic pathway signatures show coordinate expression patterns in human prostate tumors. PLoS One 3, e1816 (2008).

    Article  Google Scholar 

  21. Bild, A.H. et al. Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature 439, 353–357 (2006).

    Article  CAS  Google Scholar 

  22. Guo, J., Jin, J. & Cooper, L.F. Dissection of sets of genes that control the character of wnt5a-deficient mouse calvarial cells. Bone 43, 961–971 (2008).

    Article  CAS  Google Scholar 

  23. Krivtsov, A.V. et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 442, 818–822 (2006).

    Article  CAS  Google Scholar 

  24. Radich, J.P. et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc. Natl. Acad. Sci. USA 103, 2794–2799 (2006).

    Article  CAS  Google Scholar 

  25. Zhao, C. et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 458, 776–779 (2009).

    Article  CAS  Google Scholar 

  26. Bullinger, L. et al. Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia. N. Engl. J. Med. 350, 1605–1616 (2004).

    Article  CAS  Google Scholar 

  27. Metzeler, K.H. et al. An 86-probe-set gene-expression signature predicts survival in cytogenetically normal acute myeloid leukemia. Blood 112, 4193–4201 (2008).

    Article  CAS  Google Scholar 

  28. Mullighan, C.G. et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature 453, 110–114 (2008).

    Article  CAS  Google Scholar 

  29. Viswanathan, S.R. et al. Lin28 promotes transformation and is associated with advanced human malignancies. Nat. Genet. 41, 843–848 (2009).

    Article  CAS  Google Scholar 

  30. Kang, H. et al. Gene expression classifiers for relapse-free survival and minimal residual disease improve risk classification and outcome prediction in pediatric B-precursor acute lymphoblastic leukemia. Blood 115, 1394–1405 (2009).

    Article  Google Scholar 

  31. Rocnik, J.L. et al. Roles of tyrosine 589 and 591 in STAT5 activation and transformation mediated by FLT3-ITD. Blood 108, 1339–1345 (2006).

    Article  CAS  Google Scholar 

  32. Scholl, C. et al. Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells. Cell 137, 821–834 (2009).

    Article  CAS  Google Scholar 

  33. Kalaitzidis, D. & Neel, B.G. Flow-cytometric phosphoprotein analysis reveals agonist and temporal differences in responses of murine hematopoietic stem/progenitor cells. PLoS One 3, e3776 (2008).

    Article  Google Scholar 

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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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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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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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