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.Human tumours frequently show deregulated expression of the c-Myc proto-oncogene [1][2][3] . In Burkitt's lymphoma, this deregulation occurs through reciprocal translocations that juxtapose c-Myc with an immunoglobulin (Ig) promoter, leading to gross overexpression of c-Myc messenger RNA in the B cell lineage 4,5 . In addition, point mutations are often found in the translocated MYC alleles, clustering in a conserved region known asMYC box I (refs 6-8). Although some mutations can increase MYC stability and transforming activity in vitro, their impact on the pathogenesis of Burkitt's lymphoma is unclear [9][10][11][12][13][14][15][16] . In fact, Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. Correspondence and requests for materials should be addressed to S.W.L. (lowe@cshl.org). * These authors contributed equally to this work.Supplementary Information is linked to the online version of the paper at www.nature.com/nature.The authors declare no competing financial interests. HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript translocated c-Myc genes are subject to hypermutation in vivo that can also alter non-coding sequences, raising the possibility that these mutations are a consequence and not a cause of tumour development 17,18 .To examine the effects of MYC mutation on lymphoma development in vivo, we used a system for rapidly generating tissue-specific transgenic mice (see Supplementary Fig. 1). Two mutant MYC alleles commonly observed in Burkitt's lymphoma (P57S and T58A) 13 were cloned into a murine stem cell virus (MSCV)-based vector that co-expresses green fluorescent protein (GFP). Haematopoietic stem cells (HSCs) derived from normal fetal livers were transduced with retroviruses expressing either wild-type or mutant MYC, and the genetically modified stem cells were then used to reconstitute the haematopoietic system of lethally irradiated recipient animals. This adop...

Epstein-Barr Virus-Induced Resistance to Drugs That Activate the Mitotic Spindle Assembly Checkpoint in Burkitt's Lymphoma Cells

“…It is evident that the EBNA3 proteins do not suppress apoptosis per se. Nevertheless, since the level of the proapoptotic factor Bim is a determinant of sensitivity to taxol in breast epithelial cells and can influence the pathogenesis of BL (8,11,27), it is probable that the down-regulation of Bim levels by EBV plays a role in the development of resistance to spindle poisons in the BL cells studied here. The data shown are consistent with one or more of the EBNA3 proteins reducing Bim expression and increasing cell survival by this and perhaps other means.…”

“…It has been shown previously that the BH3-only proapoptotic protein Bim may be a major determinant of sensitivity to spindle-disrupting drugs in transformed epithelial cells (27). Bim is also particularly important in the regulation of apoptosis during B-cell development, and its regulation by cMyc can play an important role in the pathogenesis of BL (8,11,26). Furthermore, a recent report indicated that EBV-converted BL41 and Ramos cells express lower levels of Bim than the parental lines (7).…”

The p53–Bcl-2 connection

“…55,56 Similarly, tumor-derived Myc mutants that show impaired Bim activation, but normal p53 induction, are highly tumorigenic. 57 This also appears to be the case in human Burkitt's lymphoma, where both Bim and p53 deregulation exist, but are mutually exclusive. Thus, p53-dependent and independent signals act in parallel to promote cell death and suppress tumorigenesis.…”

Liposome-mediated Induction of Apoptosis of Human Hepatoma Cells by C-Myc Antisense Phosphorothioate Oligodeoxynucleotide and 5-Fluorouracil

“…Inhibition of c-myc expressions can block cells from the G1 phase into the S phase, which leads to G0/G1 blockage and inhibits rapid proliferation of tumor cells thenlead to cell apoptosis (Hemann et al, 2005). Besides, inhibition of c-myc expressions may induce apoptosis via the following mechanisms: (1) it triggers the normal differentiation of cells (Jain et al, 2002).…”