Cooperative Events in the Evolution of Monosomy 7 Myelodysplastic Syndrome
Abstract
Background and Hypothesis: The blood and immune systems of humans are essential for normal life: red blood cells, produced in the bone marrow, distribute oxygen to the cells of the body; the immune system fights off infections. Bone marrow failure is a serious medical problem with an array of different causes, degrees of severity, and outcomes. Myelodysplastic syndrome (MDS) is the most common type of bone marrow failure, currently affecting 60,000- 170,000 individuals in the United States, and the incidence is going up as our population ages. The associated costs for transfusions and medications add nearly a billion dollars to our health-care costs per year. One in three MDS patients will progress to acute myeloid leukemia (AML), a highly lethal neoplasm with costly bone marrow transplantation as the most assured therapy. Thus, additional research is needed on MDS to identify better treatment strategies. Within MDS, cases harboring only one copy of chromosome 7 (this is one of the 23 human chromosomes, and usually there are two copies) are among those with greatest resistance to therapy and risk of progression to AML and death. Importantly, researchers do not understand how this chromosome loss occurs, why it emerges within the bone marrow, and what it contributes to the myelodysplastic process. From our team’s and others’ analysis of human MDS, several associations have emerged: (1) cases of MDS with only one copy of chromosome 7 are associated with overexpression of a gene called MECOM, and (2) these cases with one chromosome 7 are associated with expression of a shortened form of blood cell growth factor. Our objective is to take these observations made in human MDS and test their importance using engineered mouse models, focusing on the causes and progression of bone marrow failure. The critical question is: How does the bone marrow progress from its normal functioning state to poor-prognosis MDS in which there is loss of chromosome 7? What genetic steps are involved, that allow these mutant cells to emerge? Genetically engineered mice provide powerful models for human disease, especially those of the bone marrow and blood system. This is because the blood systems of mice and humans are actually quite similar, and while the spectra of blood and bone marrow diseases to which mice and humans are susceptible are different, they have critical points in common. Our lab has engineered several innovative mouse strains specifically to test the genetic steps involved in MDS. In one mouse strain, we can turn on a key cancer gene in the bone marrow by feeding the mice a commonly used antibiotic. In a second strain, we can select for cells that have lost the mouse equivalent of chromosome 7. Using these tools, we intend to test our hypothesis that overexpression of this cancer gene, together with the loss of chromosome 7, leads to the development of MDS. Innovation: This type of study has never been performed and is a highly innovative use of mouse models to answer a clinically critical question concerning bone marrow failure. We have a track record of designing and implementing mouse models for human disease; our strategy takes advantage of powerful genetic tools available in the mouse to recreate the genetic lesions seen in human MDS. Impact: The impact of this will be considerable, as it will answer a critical question not previously addressed concerning the evolution of MDS cases in which there has been loss of chromosome 7. We are hopeful that new ideas for therapy can emerge from these studies: Specifically, we hope to uncover what cellular signaling pathways are important and what weaknesses in these can be targeted with existing or emerging therapies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210550
Entities
People
- Archibald S Perkins
Organizations
- United States Army
- University of Rochester