Titles + affiliations
Predicting and Preventing Therapy-Related Myeloid Neoplasm in Multiple Myeloma Patients Undergoing Stem Cell Transplantation
Therapy-related myeloid neoplasm (t-MN) is a leukemia that develops following DNA-damaging therapies. t-MN is one of the most aggressive malignancies with no effective therapies, making early prediction and prevention critical. Multiple myeloma (MM) patients who develop t-MN after undergoing stem cell transplantation (SCT) provide a unique insight into t-MN pathogenesis. MM patients are at 12-fold higher risk of t-MN compared to general population, suggesting genetic predisposition. This risk increases to 100-fold in patients undergoing SCT, suggesting that selection pressure exerted by chemotherapy also contributes to t-MN. We performed targeted sequencing and methylation analysis using paired samples obtained pre-SCT and at t-MN diagnosis and showed that those that develop t-MN (cases) have a unique genetic and methylation profile compared to matched-controls years prior to developing t-MN. Whether pharmacological intervention targeting these differences can prevent and treat t-MN is not known. In aim 1, we will investigate if hematopoietic stem cell (HSC)-intrinsic factors such as TP53-defiient state and spindle assembly checkpoint (SAC) may be present years prior to leukemic transformation, and whether SAC inhibitors can be used for prevention or therapy. In aim 2, we will study how melphalan, directly or by increasing 8-oxoguanine incorporation, predisposes to chromosomal breaks. We will study if MTH1 inhibitor, by reducing 8-oxoG incorporation prevents t-MN.
With the help of the Leukemia Research Foundation New Investigator Award, I have made significant progress towards setting up an independent and sustainable research program focusing on the improving outcomes for patients with therapy-related myeloid neoplasms (t-MN). I have established deep collaborations with leaders in the field, significantly strengthening research capabilities. The Award has facilitated publication of manuscripts and presentations. The generous Leukemia Research Foundation funding has allowed me to generate exciting preliminary data and recruit motivated personnel. With that, I was able to submit two Department of Defense grants in the year 2022. My current goal is to submit to R-01 grants in the first half of 2023. These research projects will address one of the largest unmet needs of the leukemia field -- the development of the TP53mut leukemia. Given its increasing prevalence and abysmal outcomes, improving the outcomes of TP53mut leukemia is critical in improving outcomes of leukemia in general.
Leukemia Research Foundation grant
$100K awarded in 2021
Acute myeloid leukemia (AML)
Myelodysplastic syndromes (MDS)
Causes/risk factors (MDS)