Ley studies the molecular pathogenesis of Acute Myeloid Leukemia (AML). He and his colleagues sequenced the first human cancer genomes from patients with AML, and led The Cancer Genome Atlas study of AML patients. These studies established the mutational landscape of AML, and many of the epigenetic events that are important for its pathogenesis. DNMT3A, which encodes one of the two de novo DNA methyltransferases, is one of the most common AML-initiating mutations, occurring in a third of patients with normal karyotype disease. DNMT3A mutations are the most common cause of clonal expansion of blood cell progenitors in the elderly (“Clonal Hematopoiesis”), a condition that greatly increases the risk of developing AML. Loss of DNMT3A function leads to the development of thousands of hypomethylated regions in the genomes of hematopoietic cells, but only subtle effects on gene expression. The lab is using mouse models and state-of-the-art epigenetic techniques to fully define the consequences of DNMT3A mutations (and other AML initiating events) in hematopoietic cells, establishing the mechanisms by which missense mutations alter DNMT3A activities, and exploring ways to restore normal DNMT3A function in hematopoietic cells with these mutations. Ley leads a long-standing NCI Program Project Grant (“Genomics of AML”) that is currently engaged in a comprehensive proteogenomic and immunologic characterization of all major AML subtypes, using long-read DNA and RNA sequencing, coupled with deep scale proteomics, to better define gene and protein dysregulation that contribute to pathogenesis and the clinical features of this disease. 

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Hemoglobinopathies, acute and chronic myeloid leukemias, cancer genomis, cytotoxic lymphocytes

I have mentored 22 PhD thesis students and more than 40 post-docs, most of whom have remained in academia. I have also mentored dozens of undergrads and Post-bac students, all of whom have moved on to professional schools. I have received mentoring awards from the American Society of Hematology and Washington University. I have completed the mentorship training module from the University of Minnesota.