The Role of Tumor Heterogeneity in Relapse of Pediatric Acute Myeloid Leukemia
Background: Acute leukemia is the most common childhood cancer and remains highly lethal. Even with the best treatments, almost half of children with acute myeloid leukemia (AML) do not survive. Survival rates of pediatric AML have remained distressingly static for the past two decades. A key barrier to improving outcomes in pediatric AML is understanding relapsed disease, which is a major driver of mortality. Certain genetic changes, or mutations, in leukemia cells make them more likely to relapse. One of these is a mutation in FLT3, the most commonly mutated gene in pediatric AML. But leukemias have multiple mutations at the same time; how mutations work together and/or change between diagnosis and relapse is not well understood. The technology to investigate these mutations now allows us to look at mutations within a single cell. We are using this technology to teach us how pediatric AML changes to become drug resistant, relapsed disease.
Project Goal: In piloting this approach, we identified mutations associated with drug resistance that are present in small numbers even prior to starting therapy. These include mutations in RAS— the second most commonly mutated gene in pediatric AML. We will continue to look at pediatric leukemia to define changes leading to therapy resistance and relapse. We will then look more specifically at how FLT3 and RAS work together to cause treatment resistance. In this way, we will define the genetics of relapse in pediatric AML and contribute a molecular understanding of drug resistance. Ultimately, this will suggest therapies most likely to cure children with an otherwise dismal prognosis.
Project Update 2023: We have analyzed, with single cell sequencing technology, leukemia samples from every patient treated on the most recently closed COG AML clinical trial who had serial samples available. Looking at the genetics of these leukemias has taught us about resistance mechanisms to combination therapy with traditional chemotherapy with targeted agents as well as the populations of leukemia that drive relapsed disease. We have confirmed that relapsed disease may, in many cases, be associated with the two most commonly mutated genes in pediatric AML: FLT3 and RAS. We have further interrogated how these genetic changes drive resistance to standard of care therapy. This has led us to the suggestion of new drug combinations that could improve leukemia’s sensitivity to current treatments with minimal additional toxicity.
