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Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants

Abstract

The c-Myc oncoprotein promotes proliferation and apoptosis, such that mutations that disable apoptotic programmes often cooperate with MYC during tumorigenesis. Here we report that two common mutant MYC alleles derived from human Burkitt's lymphoma uncouple proliferation from apoptosis and, as a result, are more effective than wild-type MYC at promoting B cell lymphomagenesis in mice. Mutant MYC proteins retain their ability to stimulate proliferation and activate p53, but are defective at promoting apoptosis due to a failure to induce the BH3-only protein Bim (a member of the B cell lymphoma 2 (Bcl2) family) and effectively inhibit Bcl2. Disruption of apoptosis through enforced expression of Bcl2, or loss of either Bim or p53 function, enables wild-type MYC to produce lymphomas as efficiently as mutant MYC. These data show how parallel apoptotic pathways act together to suppress MYC-induced transformation, and how mutant MYC proteins, by selectively disabling a p53-independent pathway, enable tumour cells to evade p53 action during lymphomagenesis.

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Figure 1: Tumour-derived MYC mutants show enhanced oncogenicity in vivo.
Figure 2: Wild-type and mutant MYC show apoptotic, but not proliferative, differences in vivo.
Figure 3: Impaired Bim induction contributes to the increased oncogenicity of mutant MYC alleles.
Figure 4: Impact of mutations in MYC on p53 tumour suppressor action and Bim induction in human Burkitt's lymphomas.

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Acknowledgements

We thank M. S. Jiao, C. Rosenthal, M. Yang, S. Ray, C. Yang and I. Linkov for technical assistance and J. Zilfou, R. Dickins, E. Cepero, M. Spector, J. Fridman and other members of the Lowe laboratory for advice and/or critical reading of the manuscript. We also thank A. Hunt and G. Evan for helpful advice, and T. Mak and A. Strasser for mice. This work was supported by a postdoctoral fellowship from the Helen Hay Whitney Foundation (M.T.H.), an NCI postdoctoral training grant (A.B.), a program project grant from the National Cancer Institute (W.P.T and S.W.L.) and a grant from the Irving Hansen Memorial Foundation (W.P.T). W.P.T. is a Leukemia and Lymphoma Society Scholar and S.W.L. is an AACR-NCRF Research Professor.

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Correspondence to Scott W. Lowe.

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Supplementary information

Supplementary Figure 1

This figure shows a diagram of the adoptive transfer strategy, as well as diagrams of the retroviral vectors used. (Canvas image, 248KB) (PDF 90 kb)

Supplementary Figure 2

This figure shows immunohistochemistry staining of lymphoma cells. It also shows GFP histograms of cells before and after stem cell reconstitution. (Canvas image, 1.3MB) (PDF 237 kb)

Supplementary Figure 3

This figure shows western blot analysis of FL5.12 pre-B cells. It also shows PCR analysis of DJ recombination to assess tumor clonality. (Canvas image, 1.4MB) (PDF 702 kb)

Supplementary Table

A table showing the p53 and MYC status of 31 Burkitt lymphomas. (MS Word file, 12KB) (RTF 8 kb)

Supplementary Figure Legend

A file containing figure legends for the Supplementary Figures. (MS Word file, 8KB) (RTF 6 kb)

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Hemann, M., Bric, A., Teruya-Feldstein, J. et al. Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants. Nature 436, 807–811 (2005). https://doi.org/10.1038/nature03845

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