Work

Consecutive epigenetically-active agent combinations act in ID1-RUNX3-TET2 and HOXA pathways for Flt3ITD+ve AML

Year: 2017

Type: article

Abstract: // Hamid Sayar 1,* , Yan Liu 4,* , Rui Gao 4 , Mohammad Abu Zaid 1 , Larry D. Cripe 1 , Jill Weisenbach 5 , Katie J. Sargent 5 , Mehdi Nassiri 2 , Lang Li 3 , Heiko Konig 1 , Attaya Suvannasankha 1 , Feng Pan 4 , Rajasubramaniam Shanmugam 1,7 , Chirayu Goswami 3 , Reuben Kapur 4 , Mingjiang Xu 4 and H. Scott Boswell 1,6 1 Indiana University Melvin and Bren Simon Cancer Center, Department of Medicine, Hematology/Oncology Division, Indiana University School of Medicine, Indianapolis, IN, USA 2 Department of Hematopathology, Indiana University School of Medicine, Indianapolis, IN, USA 3 Biostatistics and Computational Biology, Indiana University School of Medicine, Indianapolis, IN, USA 4 Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA 5 Indiana University Health Systems, Indianapolis, IN, USA 6 Veterans Affairs Medical Center, Indianapolis, IN, USA 7 ICMR, National Institute for Research in Tribal Health, Jabalpur, India * These authors contributed equally to this work Correspondence to: Hamid Sayar, email: // Yan Liu, email: // Keywords : AML; sorafenib; vorinostat; bortezomib; epigenetics Received : August 25, 2017 Accepted : October 25, 2017 Published : December 25, 2017 Abstract Co-occurrence of Flt3ITD and TET2 mutations provoke an animal model of AML by epigenetic repression of Wnt pathway antagonists, including RUNX3, and by hyperexpression of ID1, encoding Wnt agonist. These affect HOXA over-expression and treatment resistance. A comparable epigenetic phenotype was identified among adult AML patients needing novel intervention. We chose combinations of targeted agents acting on distinct effectors, at the levels of both signal transduction and chromatin remodeling, in relapsed/refractory AML’s, including Flt3ITD+ve, described with a signature of repressed tumor suppressor genes, involving Wnt antagonist RUNX3 , occurring along with ID1 and HOXA over-expressions. We tracked patient response to combination of Flt3/Raf inhibitor, Sorafenib, and Vorinostat, pan-histone deacetylase inhibitor, without or with added Bortezomib, in consecutive phase I trials. A striking association of rapid objective remissions (near-complete, complete responses) was noted to accompany induced early pharmacodynamic changes within patient blasts in situ, involving these effectors, significantly linking RUNX3 /Wnt antagonist de-repression (80%) and ID1 downregulation (85%), to a response, also preceded by profound HOXA9 repression. Response occurred in context of concurrent TET2 mutation/hypomorphy and Flt3ITD+ve mutation (83% of complete responses). Addition of Bortezomib to the combination was vital to attainment of complete response in Flt3ITD+ve cases exhibiting such Wnt pathway dysregulation.

Source: Oncotarget

DOI: 10.18632/oncotarget.23655