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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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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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.
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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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DOI: https://doi.org/10.1038/nature09171
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