Abstract B16: Phenotypic plasticity in the EML cell culture system as a result of HSP90 inhibition

Abstract

Abstract The process of canalization whereby phenotypic traits are buffered against stochastic fluctuations to preserve the evolutionarily advantageous “normal” level can be potentially exploited during cancer progression. Release of canalization through pharmacologic or genetic down-regulation of Hsp90 removes this buffer and increases variation, allowing for rapid changes in traits as evidenced in Drosophila, Arabidopsis, and maize. If cancer is viewed as a Darwinian struggle of the premalignant cell to acquire the hallmarks of a fully malignant cell or be extinguished, then increasing variation or heterogeneity has a beneficial effect on the fitness of the premalignant cell. It is the goal of this work to test the hypothesis that Hsp90-derived canalization, though its ability to buffer phenotypic variance and thus reduce cell plasticity, is involved in hematopoietic cell differentiation. Furthermore, we wish to determine if the canalization mechanism has an epigenetic component. We are currently using a murine hematopoietic stem cell culture system, EML cells, to investigate this hypothesis. EML cells have been induced to differentiate into macrophage and granulocyte lineages with and without pharmacologic inhibition of HSP90 through 17-AAG. We found that 17-AAG treatment increases the ability of these differentiating cells to survive in a selective medium, during culturing conditions that suggest an epigenetic mechanism. If our hypothesis is true, then loss of canalization could be a potentially powerful mechanism driving cancer progression. Fully understanding the mechanism involved would allow for new therapeutic insights and provide vital information regarding the use of HSP90 inhibitors. Citation Format: Jennifer Napper, Vincent E. Sollars. Phenotypic plasticity in the EML cell culture system as a result of HSP90 inhibition. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr B16.