Genes & Development: Lineage of origin in rhabdomyosarcoma informs pharmacological response
Jinu Abraham1, Yaiza Nuñez-Álvarez2, Simone Hettmer3,4, Elvira Carrió2, Hung-I Harry Chen5, Koichi Nishijo5, Elaine T. Huang1, Suresh I. Prajapati5, Robert L. Walker6, Sean Davis6, Jennifer Rebeles5, Hunter Wiebush5, Amanda T. McCleish5, Sheila T. Hampton5, Christopher R.R. Bjornson7, Andrew S. Brack7, Amy J. Wagers3, Thomas A. Rando7, Mario R. Capecchi8, Frank C. Marini9, Benjamin R. Ehler10, Lee Ann Zarzabal10, Martin W. Goros10, Joel E. Michalek10, Paul S. Meltzer6, David M. Langenau11, Robin D. LeGallo12, Atiya Mansoor13, Yidong Chen5,10, Mònica Suelves2, Brian P. Rubin14 and Charles Keller1,15
Abstract
Lineage or cell of origin of cancers is often unknown and thus is not a consideration in therapeutic approaches. Alveolar rhabdomyosarcoma (aRMS) is an aggressive childhood cancer for which the cell of origin remains debated. We used conditional genetic mouse models of aRMS to activate the pathognomonic Pax3: Foxo1 fusion oncogene and inactivate p53 in several stages of prenatal and postnatal muscle development. We reveal that lineage of origin significantly influences tumor histomorphology and sensitivity to targeted therapeutics. Furthermore, we uncovered differential transcriptional regulation of the Pax3: Foxo1 locus by tumor lineage of origin, which led us to identify the histone deacetylase inhibitor entinostat as a pharmacological agent for the potential conversion of Pax3: Foxo1-positive aRMS to a state akin to fusion-negative RMS through direct transcriptional suppression of Pax3: Foxo1.
Keywords
Since 2004, UT Health San Antonio, Greehey Children’s Cancer Research Institute’s (Greehey CCRI) mission has been to advance scientific knowledge relevant to childhood cancer, contribute to understanding its causes, and accelerate the translation of knowledge into novel therapies. Greehey CCRI strives to have a national and global impact on childhood cancer by discovering, developing, and disseminating new scientific knowledge. Our mission consists of three key areas — research, clinical, and education.
Stay connected with the Greehey CCRI on Facebook, Twitter, LinkedIn, and Instagram.