Abstract A47: Gene regulation by Myc during B cell activation

Myc is required for the response of cells to proliferative stimuli, as shown for example in fibroblasts or B-cells. Cellular activation entails the regulation of specific transcriptional programs concomitant with a general increase in RNA production (also termed “amplification”), which will need to be carefully disentangled for a full understanding of the mitogenic response. Upon activation of quiescent fibroblasts with serum, c-myc is rapidly induced, and is required for the subsequent activation of a set of ca. 300 genes (Myc-Dependent Serum Response, or MDSR genes) in the early-mid G1 phase of the cell cycle (1). This is followed by RNA amplification, concomitant with the G1-S transition (2). Deletion of the c-myc gene prior to serum stimulation led to a loss of all of these responses: these data indicated that Myc primarily acts to selectively regulate specific gene programs, with RNA amplification occurring as a secondary consequence (2). This is in apparent contrast with previous studies on B-cells and tumors, in which Myc was proposed to directly drive transcriptional amplification at all active loci (3, 4). Here, we addressed Myc-dependent responses in primary mouse B-cells, based on conditional deletion of c-myc followed by LPS stimulation. Our data indicate that, as in fibroblasts, a discrete set of Myc-dependent genes can be identified in B-cells: the response of these genes occurs prior to general RNA amplification, and is not entirely attributable to overt promoter/enhancer invasion by Myc. Together with our previous studies (see poster by A. Sabo et al.) (2), these data provide a unifying view of Myc9 s action in different cell types, with amplification occurring as an indirect effect, following from the action of specific Myc-target genes on cellular physiology and metabolism. Systematic work is needed to unravel which of the numerous Myc-regulated genes are critical in mediating this chain of events. References: 1. Perna D, et al. (2012) Genome-wide mapping of Myc binding and gene regulation in serum-stimulated fibroblasts. Oncogene 31, 1695-1709. 2. Sabo A, et al. (2014) Selective transcriptional regulation by Myc in cellular growth control and lymphomagenesis. Nature 511, 488-492. 3. Nie Z, et al. (2012) c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell 151, 68-79. 4. Lin CY, et al. (2012) Transcriptional amplification in tumor cells with elevated c-Myc. Cell 151, 56-67. Citation Format: Alessandra Tesi, Arianna Sabo, Valerio Bianchi, Marco Morelli, Mattia Pelizzola, Bruno Amati. Gene regulation by Myc during B cell activation. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A47.