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Regulation of myeloid leukaemia by the cell-fate determinant Musashi

Nature volume 466, pages 765–768 (2010)Cite this article

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Abstract

Chronic myelogenous leukaemia (CML) can progress from a slow growing chronic phase to an aggressive blast crisis phase1, but the molecular basis of this transition remains poorly understood. Here we have used mouse models of CML2,3 to show that disease progression is regulated by the Musashi–Numb signalling axis4,5. Specifically, we find that the chronic phase is marked by high levels of Numb expression whereas the blast crisis phase has low levels of Numb expression, and that ectopic expression of Numb promotes differentiation and impairs advanced-phase disease in vivo. As a possible explanation for the decreased levels of Numb in the blast crisis phase, we show that NUP98–HOXA9, an oncogene associated with blast crisis CML6,7, can trigger expression of the RNA-binding protein Musashi2 (Msi2), which in turn represses Numb. Notably, loss of Msi2 restores Numb expression and significantly impairs the development and propagation of blast crisis CML in vitro and in vivo. Finally we show that Msi2 expression is not only highly upregulated during human CML progression but is also an early indicator of poorer prognosis. These data show that the Musashi–Numb pathway can control the differentiation of CML cells, and raise the possibility that targeting this pathway may provide a new strategy for the therapy of aggressive leukaemias.

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Figure 1: Expression of Numb impairs blast crisis CML development.
Figure 2: The RNA-binding protein Musashi is highly expressed in immature normal and leukaemic cells and is regulated by HoxA9.
Figure 3: Loss of Musashi impairs the development and propagation of blast crisis CML
Figure 4: Musashi expression is upregulated during human CML progression.

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Acknowledgements

We thank A. M. Pendergast, J. Chute, K. Itahana, L. Penalva and L. Grimes for advice and reagents; K.-i. Yamamura for the Msi2 gene-trap mice; T. Honjo for the Rbpj conditional mice; N. Gaiano for the TNR mice; D. Baltimore for the lentiviral shRNA constructs; and A. Means and B. Hogan for comments on the manuscript. We also thank M. Cook, B. Harvat and L. Martinek for cell sorting; M. Fereshteh for advice on analysis of patient samples; D. McDonnell and H. Wade for advice on ChIP experiments; S. W. Tian for help in collecting patient samples and A. Chen and S. Honeycutt for technical help. The BCR–ABL construct was a gift from W. Pear and the NUP98–HOXA9 construct a gift from G. Gilliland. T.I. is the recipient of a postdoctoral fellowship from the Astellas Foundation for Research on Metabolic Disorders, K.L.C. is the recipient of an American Heart Association predoctoral award, B.Z. received support from T32 GM007184-33 and T.R. is the recipient of a Leukemia and Lymphoma Society Scholar Award. This work was also supported by an LLS Translational Research grant and an ASH Junior Faculty Award to V.G.O., as well as NIH grants CA18029 to J.P.R., CA140371 to V.G.O., CA122206 to C.T.J. and DK63031, DK072234, AI067798, HL097767, DP1OD006430 and an Alexander and Margaret Stewart Fund grant to T.R. We are grateful for the support received from the Lisa Stafford Research Prize.

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Author notes

  1. Takahiro Ito and Hyog Young Kwon: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Takahiro Ito, Hyog Young Kwon, Bryan Zimdahl, Kendra L. Congdon, Jordan Blum, William E. Lento, Chen Zhao & Tannishtha Reya

  2. Department of Pathology, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Anand Lagoo

  3. Department of Haematology, Imperial College London, Hammersmith Hospital, London, W12 0NN, UK

    Gareth Gerrard, Letizia Foroni & John Goldman

  4. Division of Hematology, Seoul St Mary’s Hospital, The Catholic University of Korea, Seoul, Korea

    Harriet Goh, Soo-Hyun Kim & Dong-Wook Kim

  5. Department of Haematology, Singapore General Hospital, Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore

    Charles Chuah

  6. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, 98109, Washington, USA

    Vivian G. Oehler & Jerald P. Radich

  7. James P. Wilmot Cancer Center, University of Rochester School of Medicine, Rochester, 14642, New York, USA

    Craig T. Jordan

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Contributions

T.I. and H.Y.K. designed the research, performed the majority of the experiments and helped write the paper. B.Z., K.L.C., J.B., W.E.L. and C.Z. provided experimental data and help; A.L. provided histopathological analysis; C.T.J., G.G., L.F., J.G., H.G., S.-H.K., D.-W.K. and C.C. provided human patient samples and experimental advice; T.I., H.Y.K., G.G. and B.Z. defined gene expression in patient samples by PCR; and V.G.O. and J.P.R. carried out all microarray and patient outcome analyses. T.R. conceived of the project, planned and guided the research, and wrote the paper.

Corresponding author

Correspondence to Tannishtha Reya.

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Competing interests

T.I., H.Y.K., D.W.K., V.O., J.P.R. and T.R. are named inventors on a provisional patent application no. 61/178,370 titled ‘Diagnostic and treatment for chronic and acute myeloid leukemia’.

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Ito, T., Kwon, H., Zimdahl, B. et al. Regulation of myeloid leukaemia by the cell-fate determinant Musashi. Nature 466, 765–768 (2010). https://doi.org/10.1038/nature09171

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