The BET Bromodomain Inhibitors EP11313 and EP11336 Have Potent Anti-Leukemic Activity in Acute Myeloid Leukemia (AML) and Augment the Effects of All-Trans-Retinoic Acid (atra) in Vitro

Introduction - The Myc proteins are transcription factors that have essential roles in cell growth and proliferation by both positively and negatively regulating gene expression. Mutation, amplification, or activation of the MYC oncogene family is one of the most frequent events associated with cancer. In acute myeloid leukemia (AML), c-Myc is commonly activated and plays an important role in the initiation and maintenance of the disease. In particular, c-Myc is upregulated by activating mutations of the Flt3 receptor tyrosine kinase, one of the most prevalent types of mutations in AML, and also by the AML-associated fusion proteins AML1-ETO, PML/RARα, and PLZF/RARα. It has also been shown that c-Myc is negatively regulated by C/EBPα, a transcription factor essential for granulocytic differentiation, and that c-Myc expression is elevated in myeloid leukemias in which C/EBPα is mutated. Additionally, c-Myc is stabilized in AML with mutations leading to aberrant cytoplasmic localization of nucleophosmin (NPM), the most frequent genetic alteration in AML without karyotypic aberrations. Importantly, the MYC gene itself, located at 8q24, has been found to be one of the most commonly amplified regions in AML. Lastly, the importance of c-Myc in myeloid leukemogenesis has been further demonstrated by the induction of myeloid leukemias in mouse models overexpressing c-Myc in bone marrow progenitors.