Abstract
Deletions at the Trp53 locus drive cancer in part through co-deletion of other tumor suppressors.
Major finding: Deletions at the Trp53 locus drive cancer in part through co-deletion of other tumor suppressors.
Clinical relevance: 17p deletions may promote more aggressive and chemoresistant tumors than TP53 deletion alone.
Impact: Segmental chromosomal deletions may give a selective advantage through reduced dosage of multiple genes.
The TP53 tumor suppressor gene is frequently inactivated in tumors through a two-hit mechanism wherein one allele harbors a missense mutation and the other allele is deleted in a larger segmental deletion of human chromosome 17p. Because this region contains over 300 other genes, Liu, Chen, and colleagues hypothesized that the loss of other genes in this region in addition to TP53 might drive selection for chromosome 17p loss. To test this hypothesis, 17p deletion was modeled by generating mice in which Cre recombinase could induce heterozygous deletion of a 4-Mb region of mouse chromosome 11 (11B3), which is syntenic to human 17p13.1 and includes Trp53. Deletion of 11B3 in the Eμ-Myc non-Hodgkin lymphoma mouse model resulted in rapid lymphoma development, and compared with lymphomas with focal Trp53 deletion, 11B3-deleted tumors displayed a more mature B-cell type phenotype and enhanced chemotherapeutic resistance to certain agents. Similarly, in an acute myeloid leukemia model, 11B3 deletion also promoted aggressive tumors and reduced survival compared to Trp53 deletion alone, and reduced sensitivity to the BET inhibitor JQ1. In most lymphoma-associated 17p deletions, the E1F5A tumor suppressor is deleted along with TP53, suggesting that E1F5A loss may contribute to the tumorigenic effects of 17p deletion. Indeed, knockdown of both Trp53 and Eif5a produced more rapidly growing lymphomas than either alone. An shRNA library screen targeting the approximately 100 protein coding genes co-deleted with Trp53 identified 17 additional genes, including Alox15b, whose loss promoted tumorigenesis. Similar to Eif5a, knockdown of Alox15b and Trp53 accelerated tumorigenesis compared with Trp53 knockdown alone. These findings suggest that the effects of 17p deletion may not be solely attributable to p53 loss and illustrate that segmental deletion events can affect tumor progression and resistance to treatment through disruption of multiple genes.
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