Role of Epigenetic Readers in Pathogenesis and Therapy of Acute Leukemias

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a dismal survival rate of less than 30 percent and is thus a disease where novel therapeutics are urgently required. AML is highly heterogeneous at both the molecular and clinical level. However, recurrent themes of altered transcriptional and epigenetic control are evident from sequencing and mechanistic studies. Recently, critical epigenetic regulators have surfaced as mediators of leukemogenesis and potential therapeutic targets in AML and other hematological malignancies. We and others have recently demonstrated that the Bromodomain and Extra Terminal (BET) protein family of transcriptional adapter proteins are required for transformation by MLL-fusion proteins, where they facilitate the localization of aberrant transcriptional complexes to chromatin at genes critical for leukemogenesis. Furthermore, we and others have demonstrated that small molecule inhibitors, such as I-BET151 and JQ1, of the protein-protein interactions between these proteins and acetylated lysine residues in histone tails are effective in pre-clinical models of MLL leukemias. We have recently extended studies of BET inhibition to other forms of AML using I-BET151 and found a range of sensitivities across a panel of AML cell lines and patient samples with common recurrent mutations. These cell lines also demonstrate a common cellular response to MLL-fusion leukemias, with induction of apoptosis and G1/0 arrest, suggesting that similar transcriptional programs may be targeted. In further investigating this, we identified a common transcriptional program downregulated in sensitive leukemia subtypes. In addition, using diagnostic gene expression profiles, we also demonstrate that this program can classify AML patients, suggesting that the program may provide predictive biomarkers and potentially identify those patients most likely to respond to BET inhibitions. Focusing on the most common mutation in AML, mutations of the nucleophosmin gene (NPM1c mutations), we present evidence to suggest that wild-type NPM1 has an inhibitory influence on BRD4, which is relieved upon NPM1c mutation and cytosplasmic dislocation. NPM1c mutation allows upregulation of the core transcriptional program facilitating leukemia development, and this program is abrogated by I-BET therapy. Finally, we demonstrate the efficacy of I-BET151 in human cell lines, a unique murine model, and in primary patient samples of NPM1c AML. Taken together, we have used BET inhibitors as a laboratory tool to dissect out mechanisms of aberrant transcriptional control in AML. Furthermore our pre-clinical evaluation supports clinical trials of BET inhibitors across multiple AML subtypes and identifies potential predictive biomarkers of sensitivity and response to inform these studies.