Induction and Therapeutic Targeting of Human NPM1c+ Myeloid Leukemia in the Presence of Autologous Immune System in Mice
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nihms-1518113.pdf
Description
Accepted version
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Author(s)
Kaur, Mandeep
Drake, Adam
Hu, Guangan
Rudnick, Stephen
Chen, Qingfeng
Phennicie, Ryan T.
Attar, Ricardo
Nemeth, Jeffrey
Gaudet, Francois
Chen, Jianzhu
Date Issued
February 2019
Journal
Journal of immunology
Publisher
American Association of Immunologists
Citation
Kaur, Mandeep et al. "Induction and Therapeutic Targeting of Human NPM1c+ Myeloid Leukemia in the Presence of Autologous Immune System in Mice." Journal of immunology 202, 6 (February 2019): 1885-1894 © 2019 by The American Association of Immunologists
Version
Author's final manuscript
Abstract
Development of targeted cancer therapy requires a thorough understanding of mechanisms of tumorigenesis as well as mechanisms of action of therapeutics. This is challenging because by the time patients are diagnosed with cancer, early events of tumorigenesis have already taken place. Similarly, development of cancer immunotherapies is hampered by a lack of appropriate small animal models with autologous human tumor and immune system. In this article, we report the development of a mouse model of human acute myeloid leukemia (AML) with autologous immune system for studying early events of human leukemogenesis and testing the efficacy of immunotherapeutics. To develop such a model, human hematopoietic stem/progenitor cells (HSPC) are transduced with lentiviruses expressing a mutated form of nucleophosmin (NPM1), referred to as NPM1c. Following engraftment into immunodeficient mice, transduced HSPCs give rise to human myeloid leukemia, whereas untransduced HSPCs give rise to human immune cells in the same mice. The de novo AML, with CD123 + leukemic stem or initiating cells (LSC), resembles NPM1c + AML from patients. Transcriptional analysis of LSC and leukemic cells confirms similarity of the de novo leukemia generated in mice with patient leukemia and suggests Myc as a co-operating factor in NPM1c-driven leukemogenesis. We show that a bispecific conjugate that binds both CD3 and CD123 eliminates CD123 + LSCs in a T cell-dependent manner both in vivo and in vitro. These results demonstrate the utility of the NPM1c + AML model with an autologous immune system for studying early events of human leukemogenesis and for evaluating efficacy and mechanism of immunotherapeutics.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.4049/jimmunol.1800366
