SIRT5 in Acute Myeloid Leukemia

Background

Acute myeloid leukemia (AML) has the most dismal prognosis of all blood cancers. More than 70% of AML patients will succumb to their disease. Treatment is still based on a chemotherapy regimen developed three decades ago and what little progress has been made is attributable to improvements in supportive care. Although most patients initially respond to therapy, leukemia stem cells survive in sanctuary sites of the bone marrow and eventually cause relapse and death. Intense research has identified the major DNA mutations in AML, but this knowledge has not led to therapeutic breakthroughs. To overcome this stalemate, our translational research team has screened primary AML cells (donated with informed consent by patients) to identify vulnerabilities that are independent of genetic mutations and persist despite protection afforded by the bone marrow. We have discovered that cells from most of the AML patients screened to date are highly dependent on SIRT5, an enzyme that regulates energy metabolism, while similar blood cells collected from healthy volunteers are not. Although these results have given us hope, SIRT5's exact role in AML is not at all clear at this point. Our lab is following several lines of investigation to understand why AML cell survival is dependent on SIRT5, and to identify the mechanisms that link depletion or inhibition of SIRT5 with AML cell death. The potential of this project to improve treatment strategies for AML has our lab enthused. We are excited to welcome a young scientist to learn about and contribute to this research.

Student Role

If you are selected to work in our lab, you will be working closely with a senior lab member on his or her portion of this project. You will be performing a variety of experiments, including: Polymerase Chain Reaction (PCR), DNA/RNA extraction, cell viability assays, flow cytometry and immunoblots. You will be involved in assay design, experimental procedures, data analysis, and data interpretation from these experiments. You will also be required to keep detailed records in a laboratory notebook and assemble experimental summaries. When sufficient progress has been made, you will present your results at one of our weekly lab meetings. As you gain experience with techniques, you will work semi-independently with high-level supervision on routine laboratory procedures while consulting with senior lab members on new experimental designs and data interpretation.We anticipate that the selected student will be testing hypotheses about the pathways involved in AML cell death after SIRT5 depletion (through short hairpin RNA knockdown) and how SIRT5 regulation of these pathways differs between AML and normal cells. We are currently evaluating how SIRT5 knockdown leads to the generation of reactive oxygen species and subsequent apoptotic cell death in AML cells, but this may change to meet the current needs of the project. You will experience this invigorating side to research as you perform, learn, and refine techniques that you can use for years to come, all while furthering the progress of the search for a more effective treatment for AML, the most deadly of all blood cancers.

Outcomes

If we are privileged enough to work with you this summer, you will be learning first-hand how biomedical research is performed. Our close relationship to the Huntsman Cancer Hospital allows specimens obtained from cancer patients to significantly contribute to our research. This will help you learn how our research can contribute to the health and well-being of patients. While we will benefit from your hard work and enthusiasm, we will use our experience and passion to teach you techniques that will aid you in your future endeavors in biological research. You will learn the skills necessary to critically think about, analyze, find solutions to, and overcome roadblocks that lie between you and your goals. You will be introduced to the language and culture of biological science, which will allow you to communicate and assimilate in the biomedical community. You will have the opportunity to interact with researchers with a diverse set of backgrounds including PhDs, MDs, graduate students, and industry trained researchers. Due to your membership in a translational medicine lab co-directed by two exemplary faculty members with overlapping, complementary expertise in the clinic and the lab, you will learn to focus research efforts on projects with the greatest clinical potential. You will also be exposed to the grant writing and article publication processes, thereby teaching you what it takes to perform research characterized by scientific rigor. While we gain yet another vibrant member of our team, you will gain the experience necessary to open doors to future career opportunities.

Michael Deininger
Professor

Internal Medicine
College of Medicine

Michael Deininger, MD PhD and Thomas O'Hare, PhD jointly direct our laboratory. As with all of our trainees and employees, we pledge to be continually invested in the growth and development of the student awarded a SPUR fellowship. If you are selected, we will assign a senior team member to directly work with you. In addition to daily informal interactions and discussions within the lab environment, the SPUR recipient and senior team member will formally meet with the co-directors on a weekly basis to report on progress and development. We will encourage your understanding and involvement by giving you relevant articles to read, and asking for your thoughts and interpretation of data. We treat everyone in the lab as a colleague and an equal. As with all lab members, you will be subjected to intense questioning about your work, providing an opportunity for you to demonstrate your growing understanding and allow you to identify the weaker points of that understanding. Your abstract required at the end of the program will be reviewed and edited by not only your supervisor, but the lab directors as well. In addition, we are a very collaborative lab and you will find support from all the lab members to help with experimental design and execution. Philosophically, there are two overarching goals that apply to everyone in the lab, including the directors: (1) to carry out important scientific work with a high degree of experimental rigor and (2) to exhibit excellence in all forms of scientific communication.