Gain of MYC underlies recurrent trisomy of the MYC chromosome in acute promyelocytic leukemia (2024)

Sovana Adhikary, Martin Eilers (2005)

Myc genes are key regulators of cell proliferation, and their deregulation contributes to the genesis of most human tumours. Recently, a wealth of data has shed new light on the biochemical functions of Myc proteins and on the mechanisms through which they function in cellular transformation.

Graham Bignell, Chris Greenman, Helen Davies … (2010)

The cancer genome is moulded by the dual processes of somatic mutation and selection. hom*ozygous deletions in cancer genomes occur over recessive cancer genes, where they can confer selective growth advantage, and over fragile sites, where they are thought to reflect an increased local rate of DNA breakage. However, most hom*ozygous deletions in cancer genomes are unexplained. Here we identified 2,428 somatic hom*ozygous deletions in 746 cancer cell lines. These overlie 11% of protein-coding genes that, therefore, are not mandatory for survival of human cells. We derived structural signatures that distinguish between hom*ozygous deletions over recessive cancer genes and fragile sites. Application to clusters of unexplained hom*ozygous deletions suggests that many are in regions of inherent fragility, whereas a small subset overlies recessive cancer genes. The results illustrate how structural signatures can be used to distinguish between the influences of mutation and selection in cancer genomes. The extensive copy number, genotyping, sequence and expression data available for this large series of publicly available cancer cell lines renders them informative reagents for future studies of cancer biology and drug discovery.

Laura Soucek, Jonathan Whitfield, Carla Martins … (2008)

Myc is a pleiotropic basic helix-loop-helix leucine zipper transcription factor that coordinates expression of the diverse intracellular and extracellular programs that together are necessary for growth and expansion of somatic cells. In principle, this makes inhibition of Myc an attractive pharmacological approach for treating diverse types of cancer. However, enthusiasm has been muted by lack of direct evidence that Myc inhibition would be therapeutically efficacious, concerns that it would induce serious side effects by inhibiting proliferation of normal tissues, and practical difficulties in designing Myc inhibitory drugs. We have modelled genetically both the therapeutic impact and the side effects of systemic Myc inhibition in a preclinical mouse model of Ras-induced lung adenocarcinoma by reversible, systemic expression of a dominant-interfering Myc mutant. We show that Myc inhibition triggers rapid regression of incipient and established lung tumours, defining an unexpected role for endogenous Myc function in the maintenance of Ras-dependent tumours in vivo. Systemic Myc inhibition also exerts profound effects on normal regenerating tissues. However, these effects are well tolerated over extended periods and rapidly and completely reversible. Our data demonstrate the feasibility of targeting Myc, a common downstream conduit for many oncogenic signals, as an effective, efficient and tumour-specific cancer therapy.