Mentor Name: Kathleen Sakamoto

Despite advances in our understanding of the molecular biology of adult chronic myeloid leukemia (CML), very little is known about the molecular pathogenesis of pediatric CML. Development of novel and effective therapies requires in-depth characterization of the clonal heterogeneity of pediatric CML stem cells, as well as identification of the dysregulated pathways leading to disease progression. To begin to address this need we performed single cell RNA-seq (scRNA-seq) in 4 samples from pediatric CML patients and compared these data with healthy age-matched bone marrow CD34+ cells. As immune dysfunction is a recognized feature in CML, our overall hypothesis is that determining the molecular features that lead to immune dysregulation in pediatric CML will identify genes and pathways that drive the initiation and progression of pediatric CML. Based on our preliminary data, we further hypothesize that downregulation of specific HLA-related genes (distinct from adult CML) and CD74 is one mechanism by which immune recognition and inhibition of pediatric CML stem cells is decreased. We will test this hypothesis in Aim 1. In addition, in Aim 2, we will investigate additional cell surface proteins uniquely expressed on pediatric CML stem cells that could be potential targets for therapy. We propose the following aims. Specific Aim 1: To examine the role of immune regulatory genes in pediatric CML stem cells and their impact on cytotoxic T-cell response. Specific Aim 2: To perform a comprehensive surfaceome profiling of pediatric CML stem cells to identify potential targets for immunotherapy. The specific aims we propose will address these questions, increasing our understanding of pediatric CML stem cells, disease pathogenesis and potential relapse. Upon completion of this proposal, we will have drafted a molecular atlas of immune dysregulation in pediatric CML