Acute myeloid leukemia (AML) is a sudden and rapidly progressing cancer of the blood and bone marrow. Onset can occur within days or weeks, and if left untreated is fatal. AML is characterized by heterogeneous cytogenetic and genetic profiles, making it difficult to develop precise treatments targeting the various subtypes. Fewer than one-third of AML patients survive beyond five years. The mutations that cause AML block cell maturation, leading to uncontrolled growth of immature white blood cells. Differentiation therapy aims to force the maturation of those leukemic white blood cells, and clinical success has led to 5-year survival rates over 90% in certain AML subtypes. However, almost all patients eventually experience relapse.
Using a new mouse model of differentiation therapy response, remission, and relapse, Ross Dickins and his research group have recently demonstrated that AML cells can actually interconvert between immature leukemogenic and mature non-leukemogenic states, with some mature cells potentially serving as a reservoir for new leukemic growth. Importantly, they found two phenotypically distinct mature myeloid lineages in their model: AML-derived neutrophils, which are quickly cleared and do not contribute to residual disease; and AML-derived eosinophils or monocytes, which do persist, even in remission. Using genetic tools, Dickens showed that when eosinophil differentiation is selectively blocked, all AML cells in the differentiation therapy model matured into neutrophils, which significantly reduced relapse rates in the mice. In this ASPIRE grant, Dickins will be developing new treatment strategies to prevent AML relapse by looking for agents to co-administer with differentiation therapy to promote neutrophil differentiation, and for agents that eliminate AML-derived sublineages which may otherwise persist after the therapy, in order to prevent reversion to an immature leukemogenic state. These approaches have the potential to reveal novel combination therapy strategies for this highly unmet need.