Therapy-related myeloid neoplasms (t-MN), also called secondary leukemias, are aggressive blood cancers that occur in patients that have been previously treated for a primary cancer, such as breast cancer, lung cancer, or lymphoma among many other possible cancer types. While t-MN only affects <1% of patients with solid tumors, it however represents a significant fraction (~20%) of all cases with myeloid neoplasms, such as myelodysplastic syndromes (MDS) or acute myeloid leukemias (AML) (called t-MDS and t-AML). As cancer treatments and management strategies improve, more people are surviving cancer. However, the incidence of t-MN also increases across several cancer types, which poses a growing concern for long term health and survival.

The molecular underpinnings of t-MN remains poorly understood. Patients with t-MN have often been excluded from previous large-scale clinico-genomic studies of MDS or AML, resulting in unsatisfactory guidelines for managing t-MN. Our understanding of the impact of anticancer therapies on the development of t-MN, such as chemotherapy or radiation therapy, is also limited. While some treatments are mutagenic and directly responsible for the induction of genetic drivers of t-MN, others promote the selection and growth of pre-existing blood cells that have acquired mutations, a phenomenon known as clonal hematopoiesis (CH). The distinct or combined prevalence of those two mechanisms in the development of t-MN is not well understood. The role of novel therapies (e.g. targeted radionuclide therapy or PARP inhibitors) is also unclear.

This research proposal sets out to improve our understanding of the molecular pathogenicity of t-MN and to better identify cancer patients with CH mutations that might benefit from a hematological follow-up, to ultimately prevent the development of t-MN. We will (1) study the genetic heterogeneity in t-MN, describe the correlations between genetic findings and clinical history, and categorize patients into molecular subgroups of clinical relevance; (2) assess the mutagenetic or selective impact of anticancer therapies in shaping t-MN; and (3) develop clinical tools to support the identification of patients with high risk CH.