Kenan Onel

Fellow,
- Associate Professor Dept. of Pediatrics Section of Hematology/Oncology

Contact Information

Phone: (773) 702-4919
Fax: (773) 702-4919
Email: .(JavaScript must be enabled to view this email address)
Email: .(JavaScript must be enabled to view this email address)
Website: http://biomed.uchicago.edu/common/faculty/onel.html

Research

My lab studies the genetic basis of cancer susceptibility. Genetically, we are all very similar, but not identical. Some of this normal variation is insignificant, but some may have important functional consequences. Our goal is to discover the critical sources of functional heterogeneity in the pathways that are the barriers against the cellular transition from normal to cancer. We hope that these:

1. Will be clinically useful as biomakers of cancer risk by which cancer prevention
strategies can be indivualized based on each person’s unique genetic endowment.
2. Will point towards noveltargets for new rationally designed molecular
chemotherapeutics that short circuit abmormal pathways in cancer cells while
sparing cancer patients the toxicities of currently used treatments.
Cancer results from a mutation or a series of mutations that cause a cell to escape from normal regulatory controls. Cellular stresses such as DNA damage vastly increase the rate of mutation, and therefore, the likelihood of malignant transformation. Apoptosis, or programmed cell death, is the primary cellular defense against the oncogenic potential of these stresses, and so, our research has been focused upon understanding the genetics of apoptosis.

The p53 tumor suppressor is the central mediator of apoptosis. It is induced and activated by a variety of stresses, and thereupon initiates transcriptional response programs that result in apoptosis. Underscoring the importance of p53 is the observation that it is mutated in half of all cases of cancer. As would be predicted, concomitant defects in apoptosis are, in fact, a hallmark of cancer. If loss of p53 is so important for cancer, it is a paradox that p53 is almost never mutated in the most common pediatric cancer, acute lymphoblastic leukemia (ALL). This led us to hypothesize that even within the spectrum of normal, genetic variation results in heterogeneity in the p53-mediated apoptotic stress response. We found that susceptibility to DNA damage-induced apoptosis is a genetically determined program that is completely reproducible for a given individual, but which varies significantly among individuals. We have also identified several polymorphic variants within the p53 pathway that both alter the p53-mediated apoptotic response to stress, and which are associated with increased cancer risk.

We are now searching for other sources of genetic variation ? both intrinsic to the p53 pathway and extrinsic to the p53 pathway—that alter susceptibility to damage-induced apoptosis, and which may be biomarkers for cancer susceptibility, or targets for new cancer therapies. Towards this end, we have four major projects ongoing utilizing both genome-wide and candidate gene approaches.

1. The identification of the genetic determinants of apoptosis:
Using about 400 cell lines from over 30 well-characterized multigenerational pedigrees, we are employing an unbiased genome-wide strategy to map by linkage analysis the genomic loci that contain the critical genetic determinants of DNA damage-induced apoptosis. As the polymorphic sequence variants identified by this study modulate the efficiency of the apoptotic response to oncogenic stress in different individuals, they are likely to translate into clinical tests by which cancer risk can be assessed and quantified.

2. The identification of the p53 network of apoptosis:
Although a number of p53 target genes have been identified, it remains unclear how p53 regulates apoptosis. We are using a genetic approach and expression microarray analysis to identify and model the p53-dependent transcriptional network of apoptosis. Identified p53 target genes will be attractive candidates for extensive resequencing to identify functional SNPs that may be clinically significant markers of disease risk. They may also be exciting novel targets for new therapeutics.

3. The identification of novel biomarkers and therapeutic targets in pediatric leukemia:
By array-based comparative genomic hybridization, we are mapping genomic regions amplified or deleted in pediatric ALL and comparing these to genomic loci commonly amplified or deleted in adult onset ALL. correlating this with a powerful predictor of outcome, the Day 7 bone marrow analysis. These regions will very likely contain oncogenes or tumor suppressors that are under selective pressure in ALL, and which may be biomarkers predictive of outcome, or novel therapeutic targets.

4. The identification of genomic susceptibility loci in secondary leukemia:
Using both genome-wide and candidate gene approaches, we are mapping susceptibility loci for secondary AML in a large and well-characterized cohort of patients. Because these patients develop leukemia following prior treatment with DNA-damaging agents, the identification of the genetic determinants of susceptibility may lead to insights into the critical genes and pathways by which cells generally respond to mutagens and other carcinogenic stresses, and thereby prevent oncogenesis. In addition, clinically, if cancer survivors at the greatest risk for the development of t-AML can be identified at the time of their initial diagnosis, then it may be possible to alter their chemotherapeutic regimen to reflect this risk, and thereby protect them from this devastating condition.


Research Papers