search for




 

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
References
  1. Gough SM, Slape CI, Aplan PD. NUP98 gene fusions and hematopoietic malignancies: common themes and new biologic insights. Blood 2011;118:6247-57.
    Pubmed KoreaMed CrossRef
  2. Reader JC, Meekins JS, Gojo I, Ning Y. A novel NUP98-PHF23 fusion resulting from a cryptic translocation t(11;17)(p15;p13) in acute myeloid leukemia. Leukemia 2007;21:842-4.
    Pubmed CrossRef
  3. Togni M, Masetti R, Pigazzi M, et al. Identification of the NUP98-PHF23 fusion gene in pediatric cytogenetically normal acute myeloid leukemia by whole-transcriptome sequencing. J Hematol Oncol 2015;8:69.
    Pubmed KoreaMed CrossRef
  4. Ho H, Skaist AM, Pallavajjala A, et al. NUP98-PHF23 fusion is recurrent in acute myeloid leukemia and shares gene expression signature of leukemic stem cells. Leuk Res 2016;45:1-7.
    Pubmed CrossRef
  5. Gough SM, Lee F, Yang F, et al. NUP98-PHF23 is a chromatinmodifying oncoprotein that causes a wide array of leukemias sensitive to inhibition of PHD histone reader function. Cancer Discov 2014;4:564-77.
    Pubmed KoreaMed CrossRef
  6. Yip NC, Fombon IS, Liu P, et al. Disulfiram modulated ROS-MAPK and NFB pathways and targeted breast cancer cells with cancer stem cell-like properties. Br J Cancer 2011;104:1564-74.
    Pubmed KoreaMed CrossRef
  7. Lin J, Haffner MC, Zhang Y, et al. Disulfiram is a DNA demethylating agent and inhibits prostate cancer cell growth. Prostate 2011;71:333-43.
    Pubmed KoreaMed CrossRef
  8. Duan L, Shen H, Zhao G, et al. Inhibitory effect of Disulfiram/copper complex on non-small cell lung cancer cells. Biochem Biophys Res Commun 2014;446:1010-6.
    Pubmed CrossRef
  9. Liu X, Wang L, Cui W, et al. Targeting ALDH1A1 by disulfiram/copper complex inhibits non-small cell lung cancer recurrence driven by ALDH-positive cancer stem cells. Oncotarget 2016;7:58516-30.
    CrossRef
  10. Deng M, Jiang Z, Li Y, et al. Effective elimination of adult B-lineage acute lymphoblastic leukemia by disulfiram/copper complex in vitro and in vivo in patient-derived xenograft models. Oncotarget 2016;7:82200-12.
    Pubmed KoreaMed CrossRef
  11. Wagner EK, Nath N, Flemming R, Feltenberger JB, Denu JM. Identification and characterization of small molecule inhibitors of a plant homeodomain finger. Biochemistry 2012;51:8293-306.
    Pubmed KoreaMed CrossRef
  12. Szilvassy SJ, Lansdorp PM, Humphries RK, Eaves AC, Eaves CJ. Isolation in a single step of a highly enriched murine hematopoietic stem cell population with competitive long-term repopulating ability. Blood 1989;74:930-9.
    Pubmed
  13. Xu B, Shi P, Fombon IS, et al. Disulfiram/copper complex activated JNK/c-jun pathway and sensitized cytotoxicity of doxorubicin in doxorubicin resistant leukemia HL60 cells. Blood Cells Mol Dis 2011;47:264-9.
    Pubmed CrossRef
  14. Taguchi T, Masuo Y, Kogi T, Nakamichi N, Kato Y. Characterization of long-lasting Oatp inhibition by typical inhibitor cyclosporine A and in vitro-in vivo discrepancy in its drug interaction potential in rats. J Pharm Sci 2016;105:2231-9.
    Pubmed CrossRef
  15. Sipkins DA, Wei X, Wu JW, et al. In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment. Nature 2005;435:969-73.
    Pubmed KoreaMed CrossRef
  16. Krause DS, Fulzele K, Catic A, et al. Differential regulation of myeloid leukemias by the bone marrow microenvironment. Nat Med 2013;19:1513-7.
    Pubmed KoreaMed CrossRef
  17. Krause DS, Lazarides K, Lewis JB, von Andrian UH, Van Etten RA. Selectins and their ligands are required for homing and engraftment of BCR-ABL1+ leukemic stem cells in the bone marrow niche. Blood 2014;123:1361-71.
    Pubmed KoreaMed CrossRef


October 2018, 25 (2)
Full Text PDF
Citation
Send to a friend
Twitter
Facebook

Cited By Articles
  • CrossRef (0)

Author ORCID Information
  • Eun Sil Park 

Funding Information