Discovering New Drug Targets in Radiation-Induced Myeloproliferative Neoplasms
Abstract
This research project addresses the peer reviewed cancer research program topic area of myeloproliferative neoplasms (MPNs) and the Military Relevance Focus Area of ionizing radiation. Ionizing radiation causes damage to the bone marrow, the site where blood develops. Exposure to ionizing radiation can occur as the result of a catastrophic failure of a nuclear power plant or as the result of an attack with nuclear weapons. Men and women of the U.S. Armed Forces are particularly at risk for exposure to ionizing radiation because they are frequently deployed in war zones or disaster areas or work on submarines that depend on nuclear power. The goal of this project is to identify the genetic changes that occur in patients who have developed bone marrow damage as a result of exposure to ionizing radiation. The particular type of bone marrow damage is a disease called myeloproliferative neoplasm, MPN, which causes overproduction of blood cells in the early stages, but may progress to underproduction of blood and scarring of the bone marrow, primary myelofibrosis (PMF). We have identified a cohort of patients in Ukraine who were exposed to ionizing radiation as a result of the Chernobyl nuclear accident in 1986 and have subsequently developed MPNs. We have found that patients who were previously exposed to ionizing radiation have a different rate of mutation in two of the MPN-causing genes, JAK2 and MPL, from patients who were unexposed. We would like to analyze these radiation-exposed patients more closely, in comparison with the unexposed patients, to identify the genetic alterations that occurred following exposure to ionizing radiation. We propose to evaluate the prevalence of three MPN-causing disease mutations in 262 unexposed patients with MPN compared to 88 radiation exposed patients with MPN. We will also evaluate the entire protein-coding sequence of tumor DNA from patients with the most severe form of MPN, PMF, in comparison to non-tumor DNA. We will use statistical methods to see if these genetic defects are associated with more transfusion dependence or bone marrow abnormalities. To evaluate the function of the altered genes that we identify, we will study their role in blood cell production in vitro. Based on these findings, we expect to identify additional MPN-causing genes whose function we will evaluate in cell culture models. The data that we generate will help to classify MPNs and may be used to generate information on the likely patient outcome in the case of particular mutations. Currently, there is only one Food and Drug Administration-approved drug for MPNs. By improving our understanding of MPNs and identifying new drug targets, we plan to develop treatments that can be used in military personnel to protect them against MPNs in the case of an exposure to ionizing radiation. Within 2 years, we expect to generate data that will be helpful to the doctors caring for patients with MPNs. It will take several years to develop a new drug.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610591
Entities
People
- Paula G Fraenkel
Organizations
- Beth Israel Deaconess Medical Center
- United States Army