Acute myeloid leukemia (AML) is an aggressive and lethal disease characterized by the accumulation of immature blood cells in the bone marrow. Epigenetic modifying proteins are emerging as important therapeutic targets in leukemia, as they are one of the most commonly mutated class of genes in de novo AML and are targetable with small molecules. Histone reader, bromodomain containing protein 4 (BRD4) and coactivator-associated arginine methyltransferase 1 (CARM1) have both been shown to have malignant functions in leukemia. Furthermore, perturbation of these proteins has demonstrated a therapeutic potential for the treatment of AML. Recently, focused efforts have been made to develop efficacious therapeutic drugs targeting these proteins and their associated pathways to treat AML. CARM1 inhibitors are being investigated in preclinical development, while several BET inhibitors are currently being investigated in clinical trials. Several studies have identified post translational modifications of BRD4 though the functional relevance of these modifications is poorly studied. Our preliminary findings identify a novel CARM1-dependent asymmetric arginine methylation of BRD4. Moreover, our data suggest a functional CARM1-BRD4 signaling axis in which CARM1 dimethylates BRD4, which results in the regulation of subcellular localization of BRD4 and its binding to the chromatin promoting its oncogenic functions. We propose to study the role of CARM1 in regulating BRD4 function in AML cells and to understand whether this post-translation modification of BRD4 is required for leukemia initiation and maintenance in mouse models of the disease. From our preliminary data we hypothesize that the CARM1-mediated arginine methylation of BRD4 increases its localization and binding to chromatin. Furthermore, perturbations of this methylation will result in an eviction of chromatin-bound BRD4, in turn leading to improved survival through the suppression of the transcription of oncogenic genes that drive AML pathogenesis. Though we have unearthed CARM1 as an efficacious target of AML and shown its beneficial effects on depleting oncogenic signaling, the precise mechanisms in which CARM1 inhibition hinders AML development still remains a question. By studying the substrates and interacting proteins of CARM1, such as BRD4, and defining its downstream biological events, we will more fully understand the cellular machinery that drives AML and more efficiently devise therapeutic strategies. We are confident that successful completion of our proposed study will provide experimental support for the advancement of both BET and CARM1 inhibitors as a treatment for AML as well as inform the development of novel AML targeted therapies.
Acute myeloid leukemia (AML) is a lethal blood cancer in which epigenetic regulatory proteins and their regulation of chromatin function have been implicated to contribute to its development. We have recently discovered a regulatory function of a post-translation modification of an oncogenic epigenetic reader protein, BRD4. This proposal will combine mechanistic, functional and genomic approaches to further elucidate the function of this modification in order provide insight into refining and developing novel therapies to treat AML.
