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Original Article
Disulfram Treatment of NUP98-PHF23 AML Is Not Effective In Vivo : Potential Role for Hematopoietic Stem Cells Niche
Clin Pediatr Hematol Oncol 2018;25:162-9.
Published online October 31, 2018
© 2018 Korean Society of Pediatric Hematology-Oncology and Korean Society for Pediatric Neuro-Oncology

Eun Sil Park, M.D., Ph.D.1,2, Yang Jo Chung, Ph.D.1 and Peter D. Aplan, M.D., Ph.D.1

1Genetics Branch, Center for Cancer Research, National Cancer Institute/National Institute of Health, Bethesda, MD, USA,
2Department of Pediatrics and Institute of Health Science, College of Medicine, Gyeongsang National University, Jinju, Korea
Correspondence to: Eun Sil Park
Department of Pediatrics and Institute of Health Science, College of Medicine, Gyeongsang National University, 816 Jinju-daero, Jinju 52727, Korea
Tel: +82-55-750-8829
Fax: +82-55-752-9339
E-mail: espark@gnu.ac.kr
ORCID ID: orcid.org/0000-0001-9344-7191
Received September 6, 2018; Revised September 21, 2018; Accepted October 4, 2018.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Background: NUP98 has numerous partner genes of which plant homeodomain (PHD) finger protein 23 (PHF23) fusion with NUP98 (NP23) can be detected by RT-PCR in patients with cytogenetically normal acute myelogenous leukemia (AML). In this fusion transcript of NP23 PHD of PHF23 is known to specifically bind H3K4me3 residues and act as a chromatic modifier. Disulfiram (DSF) which inhibits the binding of PHD to H3K4me3 residues selectively killed NP23 myeloblasts in vitro and therefore, we planned to evaluate the efficacy of DSF in vivo.
Methods: Cultured 961C cells (CD45.2), NP23 myeloblast cells were transplanted into B57BL/6 mice (CD45.1). Using limit dilution assay the number of leukemic stem cells (LSCs) could be calculated. A certain amount of 961C cells were transplanted into B57BL/6 mice and DSF was treated after 1 week. The engraftment level was monitored with CD45.2. Kaplan Meier survival curve was used to compare the survival between therapeutic and control group.
Results: 961C cells could be transplanted without radiation in recipient mice. Calculated LSC was estimated to be 1 out of 184 cells (95% CI range, 56-609). When treated with DSF of different doses and administration routes in 961C recipient mice no survival advantage of DSF was observed in 961C transplanted immunocompetent mouse, however it was evident that engraftment level was consistent in both groups.
Conclusion: No survival advantage of DSF in 961C transplanted immunocompetent mouse was observed, however it was evident that 961C cells shared niche with normal hematopoietic stem cells (HSCs). We expect that 961C cells and transplanted recipient mice have the potential to be used as in vivo system for new drugs development as well as for research dealing with niche for normal HSCs and LSCs.
Keywords: Acute myelogenous leukemia, NUP98, PHF23, DSF, Leukemic stem cell, Hematopoietic stem cell


October 2018, 25 (2)
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