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Our research focuses on developmental pathways that regulate hematopoietic cell growth and differentiation and are disrupted in the course of neoplastic transformation, particularly in leukemias and lymphomas. We employ a variety of experimental systems for our studies ranging from molecular biology to transgenic and knockout mice. Our current interests are:1) Characterize novel families of oncoproteins (Pbx and Meis) that dimerize with and regulate the DNA binding properties of Hox proteins. We are investigating how Pbx and Meis proteins contribute to the specificity of Hox function in development and how disruption of their activities leads to neoplasia.2) We have discovered a group of oncoproteins that are implicated in long-term maintenance of gene expression through their effects on the state of chromatin. We are studying the role that normal chromatin structure plays in gene regulation in hematopoietic cells and how its disruption leads to altered development and cancer.3) We are defining the properties of cancer stem cells that initiate and sustain the unique disease features of acute leukemias through the use of various adoptive animal models.Our studies have demonstrated that several of the proteins encoded by cellular oncogenes function in fundamental aspects of gene regulation. These are frequently activated by fusion to other transcriptional proteins resulting in chimeric transcription factors. We are studying the effects and consequences of protein fusion on the transcriptional and transforming activities of these proteins using in vitro and animal models.In addition to these basic issues concerning leukemia pathogenesis, we are devising new diagnostic procedures for detecting and monitoring leukemia patients based on molecular genetic abnormalities in the malignant cells.