Mithun Shah, MD, PhD

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.