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Multi-genetic events collaboratively contribute to Pten-null leukaemia stem-cell formation

Nature volume 453, pages 529–533 (2008)Cite this article

Abstract

Cancer stem cells, which share many common properties and regulatory machineries with normal stem cells, have recently been proposed to be responsible for tumorigenesis and to contribute to cancer resistance1. The main challenges in cancer biology are to identify cancer stem cells and to define the molecular events required for transforming normal cells to cancer stem cells. Here we show that Pten deletion in mouse haematopoietic stem cells leads to a myeloproliferative disorder, followed by acute T-lymphoblastic leukaemia (T-ALL). Self-renewable leukaemia stem cells (LSCs) are enriched in the c-KitmidCD3+Lin- compartment, where unphosphorylated β-catenin is significantly increased. Conditional ablation of one allele of the β-catenin gene substantially decreases the incidence and delays the occurrence of T-ALL caused by Pten loss, indicating that activation of the β-catenin pathway may contribute to the formation or expansion of the LSC population. Moreover, a recurring chromosomal translocation, T(14;15), results in aberrant overexpression of the c-myc oncogene in c-KitmidCD3+Lin- LSCs and CD3+ leukaemic blasts, recapitulating a subset of human T-ALL. No alterations in Notch1 signalling are detected in this model, suggesting that Pten inactivation and c-myc overexpression may substitute functionally for Notch1 abnormalities2,3, leading to T-ALL development. Our study indicates that multiple genetic or molecular alterations contribute cooperatively to LSC transformation.

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Figure 1: VEC-Cre -mediated Pten loss leads to MPD and leukaemogenesis.
Figure 2: Self-renewing LSCs are enriched in the c-Kit mid CD3 + compartment.
Figure 3: β-Catenin activation in LSCs and its role in leukaemogenesis.
Figure 4: The recurring translocation T(14;15) involves the Tcra/Tcrd cluster and the c- myc gene and results in aberrant overexpression of c- myc in LSCs and T-ALL blasts.

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Acknowledgements

We thank O. Witte, K. Dorshkind, J. Said, R. Gatti, K. Sakamoto, S. Schubbert, R. Hill and B. Valamehr for helpful comments; D. Cheng from O. Witte’s laboratory for cell sorting; J. Gao for retro-orbital bleeding and genotyping; and the Department of Pathology’s Tissue Procurement Core Laboratory (partly supported by National Cancer Institute grant CA16042) for tissue procurement. W.G. is supported by a California Institute of Regenerative Medicine (CIRM) training fellowship. J.E.Y. was supported by the University of California Los Angeles Amgen Scholar Program. J.Y.C. is supported by the Beckman Undergraduate Research Program.

Author Contributions W.G. and H.W. designed the experiments, and W.G. performed a majority of the work involved in this study. J.L.L. performed immunohistochemistry on tissue sections and cytospin slides (Fig. 3a), and participated in FACS-Gal analysis, PB profile analysis and histological analysis. C.-J.C. performed RT–PCR and western blotting for c-myc expression (Fig. 4e and data not shown). X.L. maintained mouse colonies and was responsible for intravenous injection; S.M. performed western blotting and TOPflash reporter assay for β-catenin activation by c-Myc (Supplementary Fig. 9c, d). J.E.Y. performed Notch1 mutation screening and RT–PCR analysis for Fbxw7 and Hes1 expression (Supplementary Fig. 10). J.Y.C. performed Pten and Ctnnb1 genotyping and FACS analysis; Y.X. and M.V.-G. performed SKY and FISH analysis (Fig. 4a, b, d, and Supplementary Fig. 8). M.L.I.-A. provided VE-Cadherin-Cre+ mice. W.G., J.L.L. and H.W. wrote the paper. All authors discussed the results and commented on the manuscript.

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Authors and Affiliations

  1. Department of Molecular and Medical Pharmacology,,

    Wei Guo, Chun-Ju Chang, Sherly Mosessian, Xiaoman Lewis, James Y. Chen & Hong Wu

  2. Department of Pediatric Hematology/Oncology,,

    Joseph L. Lasky

  3. Department of Molecular, and,

    M. Luisa Iruela-Arispe

  4. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, Cellular and Developmental Biology, University of California, Los Angeles, Los Angeles, California 90095, USA ,

    Hong Wu

  5. Department of Medicine, Medical Oncology Division, University of Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA,

    Yun Xiao & Marileila Varella-Garcia

  6. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA,

    Jennifer E. Yeh

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Correspondence to Hong Wu.

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Guo, W., Lasky, J., Chang, CJ. et al. Multi-genetic events collaboratively contribute to Pten-null leukaemia stem-cell formation. Nature 453, 529–533 (2008). https://doi.org/10.1038/nature06933

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