THE INTEGRATED USE OF HUMAN MODELS OF LEUKEMIA TO IDENTIFY POTENTIAL THERAPEUTIC TARGETS

Abstract

Acute myeloid leukemia (AML) is a disease that results from the uncontrolled growth of primitive myeloid progenitor cells that are unable to undergo terminal differentiation. To better understand the genetic and epigenetic changes involved in leukemogenesis, we use a human model leukemia system where cord blood donor cells from a single donor are transduced with the human KMT2A-MLLT3 gene fusion to produce leukemias. We have generated multiple model leukemias and compared these to genetically matched pediatric AML patient samples that has allowed us to characterize the step-wise epigenetic and splicing changes that accompany leukemogenesis, allowing us to build an integrated view of this process. Our analysis of these data have revealed a number of candidate biomarker genes that are expressed in KMT2A translocated AMLs but not normal blood cells, some of which are important for leukemic growth. These candidate genes, which have validated diagnostic value, have also been used as targets for monoclonal antibody generation in order to assess their value as potential immunotherapeutics. Having established the value of this approach, we are now expanding our models to include additional oncogenic drivers in order to elucidate the differences in patient outcomes associated with the presence of specific fusions. Moreover, we have recently leveraged these model leukemias and matched patient samples to perform a high-throughput small molecule screen to identify novel therapeutic vulnerabilities and deconvolute the role of secondary mutations in pediatric patients. The establishment of this chemogenomic pipeline to generate, characterize, and then screen model leukemias will provide not only insight into the molecular mechanisms involved in this disease, but also how they can be rationally targeted to improve patient outcomes.