Molecular Mechanisms and Therapies for Radiation-Induced Myelodysplastic Syndrome (MDS) - Bondada Scope

Advancing age is the single biggest risk factor for developing cancers of almost all types. This is similarly true for hematologic malignancies such as leukemia, lymphoma, multiple myeloma and myelodysplastic syndrome (MDS). These diseases all arise from aberrant blood-forming stem and progenitor cells in the bone marrow. Thus, aging results in stem cell damage and cancer through mechanisms that are poorly understood. Some types of leukemia arise from stem cells in which there are characteristic chromosomal deletions or rearrangements, but in many cancers a characteristic genomic signature is not apparent, aside from a general and non-specific instability. We know little of the fundamental causes of the structural changes in chromosomes preceding cancer, but attention has recently turned to what are called epigenetic alterations in chromosomes. Epigenetic changes are more subtle and, rather than (at least initially) causing deletions and rearrangements, are manifested in aberrant silencing or activation of genes, often through methylation of the DNA. It is also known that aging is a primary cause of epigenetic changes in cells, including bone marrow stem cells. Therefore, the stage for carcinogenesis may be set during aging by predictive patterns of methylation of the DNA in the genomes of stem cells. Up to now it has not been feasible to decipher the methylation pattern of entire genomes, let alone determine whether diagnostic patterns of methylation are found between normal and cancerous stem cells. High throughput analysis of the methylation status of cells, called a “methylome”, is now possible, even for rare cells such as bone marrow stem cells. We therefore are carrying out a comprehensive analysis of the dynamic changes in the methylomes of stem cells during normal aging. We will then compare the emerging patterns with the methylomes of cells from patients with various hematologic malignancies to determine which of the aging patterns are associated with specific blood diseases, such as MDS or chronic lymphocytic leukemia. Additional funding for our studies will enable two clinically important advancements: 1. Diagnostic tests. Specific stem cell methylome patterns that emerge during aging may predispose an individual to specific malignancies. Customized medicine will soon enable the methylomes of individual patients’ stem cells to be screened for patterns that could provide the basis for a risk grading system to be used in determining appropriate treatments. 2. Clinical Treatments. The new high throughput technology used to decipher methylomes provides the additional power of determining the identities of specific genes that are inappropriately methylated (or de-methylated). Methylation of a gene is usually associated with gene silencing; therefore, molecular treatments could be customized to de-methylate pivotal genes. Alternatively, molecular tools could be customized to compensate for a silenced gene, based on knowledge of its specific function in a specific molecular pathway—a tumor suppressor, for example.