Mutational and Aging Risk Factors for Myelodysplastic Syndrome
Abstract
Myelodysplastic syndrome (MDS) is a bone marrow failure state that is acquired as people age and leads to low blood counts needing transfusion support, risk of infections, and sometimes conversion to Acute Myeloid Leukemia (AML). When MDS occurs after damage to bone marrow caused by chemotherapy or radiation as a result of cancer treatment, it is known as therapy-related myelodysplastic syndrome (t-MDS). This is a devastating complication of previous cancer therapy and is generally resistant to treatment with average cure rate of less than 10% in older patients. Most patients with MDS cannot go through bone transplant and even for those that do go through it, relapse rate is high. Large-scale gene sequencing studies in normal healthy populations have shown that people above 60 years have a high chance (30%) of having an age-related acquired mutation in peripheral blood. This condition has been termed as Clonal Hematopoiesis (CH). CH occurs as blood cells make mistakes dividing in an aging bone marrow. CH is associated with increased risk of MDS and AML as well as cardiovascular disease and it is estimated that although CH converts to blood cancer at the rate of 1% per year, majority of patients with CH don’t progress to MDS. Understanding risk factors that put a patient with CH at high risk for transformation to MDS would be a major breakthrough in early detection, intervention, and prevention of MDS. We have identified that a high risk CH gene signature increases the future risk of AML by using samples collected a decade before diagnosis of AML in a population cohort, but this risk is not absolute. The goal of this study is to determine the impact of aging risk factors in progression of CH to MDS. CH by itself is an aging-related phenomenon. It is well known that aging is linked to genetic instability and changes in gene function that can be measured by methylation clocks. These methylation clocks can be used to estimate the biological age of individuals. Some individuals can be older as measured by the methylation clock compared to their actual age. This state is termed as epigenetic age acceleration (EAA). We found that people who have CH and EAA together are more likely have increased incidence and mortality from cardiovascular disease. In addition, CH can increase inflammation in our bodies and this in turn can help propagate the CH positive cells, making it a feedback loop. Our main hypothesis is that factors related to aging (Aim 1) and inflammation (Aim 2) can help determine the progression from CH to MDS and these factors can be identified so that risk can be better assessed. To achieve these aims, we have identified two cohorts, the Women’s Health Initiative and the Multiethnic Cohort that collected blood on healthy individuals and followed them for over 20 years for any cancer diagnoses. We have identified appx 600 participants who eventually developed MDS/t-MDS and will match these individuals with healthy normal controls that never developed any blood cancer. We will perform a custom CH gene sequencing developed at Weill Cornell Medicine to determine the presence of CH in blood collected many before diagnoses of MDS/t-MDS. We will also measure aging and inflammatory factors in peripheral blood collected at the same time as the DNA for the CH testing, all before the diagnosis of MDS. By comparing the mutational, aging, and inflammatory patterns to normal unaffected controls, we will be able to create signatures that are linked to a very high risk of progression to MDS/t-MDS. Through the study, we will be able to define the aging process that distinguishes participants with CH that are at highest risk of MDS/t-MDS, which can then allow the establishment of monitoring strategies as well as form the basis of inclusion in prevention-oriented clinical trials. Currently there are some trials of anti-inflammatory drugs, vitamin C, and other targeted treatments that are being touted as ag
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310431
Entities
People
- Pinkal Desai
Organizations
- United States Army
- Weill Cornell Medicine