Abstract 4202: Genetic re-programming of the AML cell line HL-60 during differentiation: Roles of the EGR/NAB and NR4A transcription factors

HL-60 cells represent an established line of human acute myeloid leukemia cells that can be induced to differentiate along several distinct myeloid lineages. Phorbol esters activate a signaling network, which includes the protein kinase C (PKC) pathway, causing the leukemia cells to differentiate into macrophage-like cells. As the leukemia genetic program is converted to the macrophage program, the cells exit the cell cycle, undergo morphological changes, become adherent, display other macrophage properties, and ultimately initiate apoptosis. This study provides a detailed DNA microarray analysis with qRT-PCR validation of the genetic network of the leukemia cell during first 24 hours post-induction of differentiation. We present data describing the global changes in gene expression at the RNA-level at 0.5, 1, 3, 6, 12, and 24 hours post-PMA treatment and information about specific genes with regard to their RNA and protein expression levels. Approximately 2,000 genes were identified that exhibit significant changes in mRNA levels from the leukemia expression program. A cluster analysis was performed to group these genes by their pattern of expression resulting in a collection of distinct expression profiles and associated functional profiles. These genes encode transcription factors, intracellular signal transducers, receptors, cytokines and a variety of other proteins. Of particular interest in understanding the genetic re-programming of the leukemic cells is the transcription factor expression profile. In addition to the established roles of the NF-kappa-B and AP-1 transcription factors in HL-60 cell differentiation, we present possible roles for the EGR/NAB and NR4A transcription factor families in both differentiation and initiation of apoptosis. A variety of biological analysis strategies using the expression data to define regulatory groupings that characterize the changing genetic network in these cells, including interaction networks and pathway activations have been carried out. Taken together, we seek to better understand the genetic program defining leukemia cells and the mechanisms by which oncogenic mutations can be overridden to achieve cell cycle arrest, differentiation and apoptosis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4202. doi:153