title: Engraftment of Human Primary Acute Myeloid Leukemia Defined by Integrated Genetic Profiling in NOD/SCID/IL2rγnull Mice for Preclinical Ceramide-Based Therapeutic Evaluation.
abstract: Acute Myeloid Leukemia (AML) is a highly heterogeneous and poor prognosis disease with few available therapeutic options. Novel advances are urgently needed, however effective models to test experimental therapeutics have been lacking. Recently, NOD/SCID/IL2rγnull (NSG) mice were shown to engraft primary human AML in a manner that recapitulated the natural disease and its progression. Additionally, integrated genomic profiling was used to refine risk stratification of AML. In this study, we demonstrated the engraftment of molecularly defined primary AML in NSG mice. We showed that AML that express DNMT3A mutations, which predict for adverse outcome, engrafted with exceptional efficacy. Lastly, we demonstrated that human AML-engrafted NSG mice can be effectively used to study novel ceramide-based therapeutics. Ceramide is a bioactive sphingolipid that has been implicated as an inducer of apoptosis. Elevation in cancer cell ceramide levels either via exogenous delivery or by provoking intracellular ceramide generation is the goal of ceramide-based therapeutics. In this study, we used the human AML-engrafted NSG mouse model to evaluate nanoliposomal short-chain C6-ceramide and a nanoliposomal formulation of the ceramide-inducer tamoxifen. Altogether, the NSG model is likely to prove invaluable in the study of novel agents, sushc as ceramide-based therapeutics, with the ability to define therapeutic activity against specific molecularly defined and risk stratified AML.
authors.affiliation: Department of Medicine, Penn State College of Medicine, Hershey, USA; Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, USA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Barth
authors.affiliation: Department of Medicine, Penn State College of Medicine, Hershey, USA; Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, USA.
authors.forename: Nichole R
authors.initials: NR
authors.lastname: Keasey
authors.affiliation: Department of Medicine, Penn State College of Medicine, Hershey, USA; Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, USA.
authors.forename: Xujung
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Penn State College of Medicine, Hershey, USA.
authors.forename: Sriram S
authors.initials: SS
authors.lastname: Shanmugavelandy
authors.affiliation: Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, USA; Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, USA.
authors.forename: Raajit
authors.initials: R
authors.lastname: Rampal
authors.affiliation: Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, USA; Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Hricik
authors.affiliation: Department of Biochemistry and Molecular Biology, East Carolina University, Greenville, USA.
authors.forename: Myles C
authors.initials: MC
authors.lastname: Cabot
authors.affiliation: University of Virginia Cancer Center, Charlottesville, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Kester
authors.affiliation: Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, USA; Department of Pharmacology, Penn State College of Medicine, Hershey, USA; Department of Pediatrics, Penn State College of Medicine, Hershey, USA.
authors.forename: Hong-Gang
authors.initials: HG
authors.lastname: Wang
authors.affiliation: The Jackson Laboratory, Bar Harbor, USA.
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Shultz
authors.affiliation: Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, USA.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Tallman
authors.affiliation: Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, USA; Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, USA.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.affiliation: University of Virginia Cancer Center, Charlottesville, USA.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Loughran
authors.affiliation: Department of Medicine, Penn State College of Medicine, Hershey, USA; Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Claxton
keywords: Acute myeloid leukemia; Ceramide; DNMT3A; Integrated genetic profiling; NSG mouse; Nanoliposome; Tamoxifen