Editors' ChoiceOncogenes

Mutant Myc Provides a Dual Route to Cancer

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Science's STKE  16 Aug 2005:
Vol. 2005, Issue 297, pp. tw299
DOI: 10.1126/stke.2972005tw299

Burkitt lymphoma, a highly aggressive B cell malignancy, is associated with chromosomal translocations that put myc (which stimulates both cell proliferation and apoptosis) under the control of an immunoglobulin promoter, leading to its gross overexpression and thereby to enhanced cell proliferation (see Berns). Noting that translocated myc frequently contains point mutations in a conserved region, Hemann et al. used mice whose hematopoietic systems were reconstituted with hematopoietic stem cells (HSCs) transduced with wild-type myc or tumor-derived myc point mutations to investigate the possible role of these mutations in lymphomagenesis. Whereas few mice receiving stem cells that expressed wild-type myc developed lymphomas, most of those receiving stem cells that expressed myc with point mutations did; moreover, the latency of lymphoma development in the latter group was much shorter. The increase in bone marrow cell proliferation produced by wild-type and mutant Myc was similar. Mutant Myc activated the p19Arf-p53 signaling pathway as effectively as wild-type Myc but, unlike wild-type Myc, did not increase the abundance of the proapoptotic protein Bim (which inhibits Bcl-2 activity). Moreover, when expressed in HSCs lacking Bim, wild-type and mutant myc were equally effective at promoting lymphomagenesis. Immunohistochemistry indicated that Burkitt lymphomas expressing wild-type myc expressed Bim, whereas most with point mutations in Myc did not. Thus, whereas both wild-type and mutant Myc promote cell proliferation, mutant Myc also inhibits apoptosis through a Bim-dependent and p53-independent pathway and is therefore more effective at promoting lymphomagenesis.

M. T. Hemann, A. Bric, J. Teruya-Feldstein, A. Herbst, J. A. Nilsson, C. Codon-Cardo, J. L. Cleveland, W. P. Tansey, S. W. Lowe, Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants. Nature 436, 807-811 (2005). [PubMed]

A. Berns, Two in one. Nature 436, 787-789 (2005). [PubMed]

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