title: Synergistic anti-leukemic interactions between ABT-199 and panobinostat in acute myeloid leukemiaex vivo.
abstract: Cure rates for acute myeloid leukemia (AML) remain suboptimal; thus new treatment strategies are needed for this deadly disease. Poor clinical outcomes have been associated with overexpression of the anti-apoptotic Bcl-2 family proteins Bcl-2, Bcl-xL, and Mcl-1, which have garnered great interest as therapeutic targets. While the Bcl-2-selective inhibitor ABT-199 has demonstrated promising preclinical anti-leukemic activities, intrinsic drug resistance remains a problem. In our most recent study, we identified Mcl-1 sequestration of Bim as a mechanism of intrinsic resistance to ABT-199 in AML cells, thus upregulating Bim could overcome such resistance. Histone deacetylase (HDAC) inhibitors (HDACI) are a class of agents that have been confirmed to upregulate Bim. This prompted our hypothesis that combining an HDACI with ABT-199 would overcome intrinsic resistance to ABT-199 and result in synergistic anti-leukemic activity against AML. In this study, we investigated the anti-leukemic activity of panobinostat, a pan-HDACI, in combination with ABT-199 in AML cell lines and primary patient samples. We found that the combined drug treatment resulted in synergistic induction of cell death in both AML cell lines and primary patient samples. Panobinostat treatment resulted in upregulation of Bim, which remained elevated in the presence of ABT-199. In addition, shRNA knockdown of Bim in AML cell lines significantly attenuated apoptosis induced by combined panobinostat and ABT-199. Our results provide compelling evidence that Bim plays a key role in the combined anti-leukemic activity of panobinostat and ABT-199 against AML, and support clinical evaluation of combined panobinostat and ABT-199 in the treatment of AML.
authors.affiliation: Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan Detroit, MI, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Schwartz
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology & Engineering, The Ministry of Education, School of Life Sciences, Jilin University Changchun, China.
authors.forename: Xiaojia
authors.initials: X
authors.lastname: Niu
authors.affiliation: MD/PhD Program, School of Medicine, Wayne State University Detroit, MI, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Walton
authors.affiliation: Cancer Biology Graduate Program, School of Medicine, Wayne State University Detroit, MI, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Hurley
authors.affiliation: Department of Hematology and Oncology, The First Hospital of Jilin University Changchun, China.
authors.forename: Hai
authors.initials: H
authors.lastname: Lin
authors.affiliation: Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State UniversityDetroit, MI, USA; Department of Oncology, School of Medicine, Wayne State UniversityDetroit, MI, USA.
authors.forename: Holly
authors.initials: H
authors.lastname: Edwards
authors.affiliation: Division of Pediatric Hematology/Oncology, Children's Hospital of MichiganDetroit, MI, USA; Department of Pediatrics, School of Medicine, Wayne State UniversityDetroit, MI, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Taub
authors.affiliation: Division of Pediatric Hematology/Oncology, Children's Hospital of MichiganDetroit, MI, USA; Department of Pediatrics, School of Medicine, Wayne State UniversityDetroit, MI, USA.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, School of Medicine, Wayne State UniversityDetroit, MI, USA; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State UniversityDetroit, MI, USA; Department of Oncology, School of Medicine, Wayne State UniversityDetroit, MI, USA.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Ge
keywords: ABT-199; Bcl-2; Bim; acute myeloid leukemia; panobinostat