Genetic Risk Factors for Clonal Hematopoiesis and Leukemia Development Following Ionizing Radiation and Chemical Exposure
Abstract
This proposal addresses the FY15 PRCRP Topic Area of "Genetic Cancer Research" and the Fiscal Year 2015 Military Relevance Focus Area of "Military-relevant risk factors associated with cancer (ionizing radiation, chemicals, environmental carcinogens)." Exposure to ionizing radiation or to certain types of chemicals markedly increases the risk of developing leukemia. These leukemias are often difficult to treat and carry a poor prognosis. Genetic factors play a role in who will develop leukemia following radiation/chemical exposure. The overall objective of this proposal is to further understand the mechanisms that lead to radiation/chemical-induced leukemia and to identify the genetic risk factors that influence who will develop leukemia following exposure. The rationale for this study is that further understanding these mechanisms and genetic risk factors will make it possible to screen individuals at increased risk (and have them avoid activities with elevated exposure risk), to develop tests to follow exposed individuals to determine if they are developing early stages of leukemia, to design interventions to reduce the risk of progression to leukemia of exposed individuals, and to develop improved treatment strategies for the leukemias that do develop. Clues as to the mechanisms of radiation/chemical induced leukemias have come from studies of survivors of the Hiroshima atomic bombings, individuals living near the Semipalatinsk Soviet nuclear test site, and cancer patients exposed to chemotherapy agents who developed a pre-leukemic condition called myelodysplastic syndrome. A very high proportion (40%-50%) of these individuals were found to contain mutations in the RUNX1 gene in their blood cells. Recent studies suggest RUNX1 plays a role in how cells respond to DNA damage. Normally, blood stem cells containing damaged DNA stop reproducing themselves and either repair their DNA or undergo "suicide" if the damage is beyond repair. This "checkpoint" ensures that stem cells containing DNA damage do not persist in the body. Based on recent data, we hypothesize that this checkpoint fails to occur in a small population of pre-existing blood stem cells that contain RUNX1 mutations in affected individuals. This results in the body retaining "damaged" blood stem cells that normally should be eliminated. To make matters worse, these stem cells outgrow normally healthy blood stem cells that have appropriately stalled their growth after the radiation/chemical exposure. Over time, the RUNX1 mutant blood cells predominate within the bone marrow. Since these cells are not able to repair their damaged DNA effectively, they have a high likelihood of eventually transforming into full-blown leukemia. This proposal involves developing a mouse model to test our hypothesis in detail. It will also utilize a technique in human blood cells to identify additional genes (like RUNX1) that when mutated will cause the blood cells to take over the bone marrow following exposure to ionizing radiation or DNA damaging chemicals. This proposed work involves basic science research. However, it is anticipated that positive results from this study could be applied clinically for genetic analysis of at-risk and exposed individuals within 3-5 years. Results from this study are also expected to fill in important knowledge gaps in the cancer field in general about how cells protect themselves from DNA damaging environmental stimuli. This proposal is directly relevant to members of the Armed Forces and their families because of their increased risk of exposure to ionizing radiation and DNA-damaging chemicals, particularly in the age of global terrorism.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610616
Entities
People
- Alan B Cantor
Organizations
- United States Army