alexa Engraftment of Human Primary Acute Myeloid Leukemia Def
ISSN: 2329-6917

Journal of Leukemia
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Research Article

Engraftment of Human Primary Acute Myeloid Leukemia Defined by Integrated Genetic Profiling in NOD/SCID/IL2rγnull Mice for Preclinical Ceramide-Based Therapeutic Evaluation

Brian M Barth1,2*, Nichole R Keasey1,2, Xujung Wang1,2, Sriram S Shanmugavelandy3, Raajit Rampal4,5, Todd Hricik4,5, Myles C Cabot6, Mark Kester7, Hong-Gang Wang2,3,8, Leonard D Shultz9, Martin S Tallman4, Ross L Levine4,5, Thomas P Loughran Jr.7 and David F Claxton1,2

1Department of Medicine, Penn State College of Medicine, Hershey, USA

2Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, USA

3Department of Pharmacology, Penn State College of Medicine, Hershey, USA

4Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, USA

5Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, USA

6Department of Biochemistry and Molecular Biology, East Carolina University, Greenville, USA

7University of Virginia Cancer Center, Charlottesville, USA

8Department of Pediatrics, Penn State College of Medicine, Hershey, USA

9The Jackson Laboratory, Bar Harbor, USA

*Corresponding Author:
Dr. Brian M Barth
Department of Medicine, Division of Hematology and Oncology
Penn State Hershey Cancer Institute, Penn State College of Medicine
500 University Drive, PO Box 850, CH46 Hershey, PA 17033, USA
Tel: 717-531-0003 (289457)
E-mail: [email protected]

Received date: April 4, 2014; Accepted date: July 10, 2014; Published date: July 25, 2014

Citation: Barth BM, Keasey NR, Wang X, Shanmugavelandy SS, Rampal R, et al. (2014) Engraftment of Human Primary Acute Myeloid Leukemia Defined by Integrated Genetic Profiling in NOD/SCID/IL2rγnull Mice for Preclinical Ceramide-Based Therapeutic Evaluation. J Leuk (Los Angel) 2:146. doi: 10.4172/2329-6917.1000146

Copyright: © 2014 Barth BM et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

 

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.

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