Publication list via PubMed

Regulation of N-myc Oncogene in Human Neuroblastoma

Neuroblastoma is a common childhood tumor that is usually not diagnosed until it has become widespread. Survival rates in children with advanced neuroblastoma have not enjoyed the large gains seen in other forms of pediatric cancer. Recently however, results of a national clinical trial showed that the addition of retinoic acid (RA) after conventional therapy significantly improved disease free survival.

This naturally occurring dietary compound causes neuroblastoma cells growing in culture to mature and differentiate into benign nerve cells. It is felt that this is what happens in patients treated with RA. A key event in the ability of RA to induce maturation in these cells is its effect on the MYCN gene, which plays a major role in the biology of neuroblastoma. Shutting off MYCN is the first step in getting neuroblastoma cells to stop dividing and begin the maturation process. Loss of the ability to turn down MYCN production is associated with a failure of tumor cells to differentiate in response to RA treatment.

Despite its importance in understanding how differentiation therapy might work, nothing is known about the molecular switch that turns the MYCN gene off after tumor cells get exposed to RA. Traditional methods of gene analysis have not been able to address this question because they only focus on a small region of DNA at a time. Work in this lab uses new analytical techniques that allow the simultaneous examination of multiple sites along the MYCN gene’s control region, as well as the detection of regions on other chromosomes that might interact with the MYCN control region. It is hoped that this approach will identify DNA regions that interact in a cooperative fashion to shut the gene off, and that knowledge of these DNA sequences will lead to the identification of the regulatory proteins that bind to them. Such information will ultimately enable the development of molecular tests to determine which patients have tumors that might be resistant to RA, and may provide leads as to alternative therapeutic approaches. These patients could then be triaged to receive other drugs instead of or in addition to RA that would increase their chances of staying in remission.