Abstract
Chemoresistance may be due to the survival of leukemia stem cells (LSCs) that are quiescent and not responsive to chemotherapy or lie on the intrinsic or acquired resistance of the specific pool of AML cells. Here, we found, among well-established LSC markers, only CD123 and CD47 are correlated with AML cell chemosensitivities across cell lines and patient samples. Further study reveals that percentages of CD123+CD47+ cells significantly increased in chemoresistant lines compared to parental cell lines. However, stemness signature genes are not significantly increased in resistant cells. Instead, gene changes are enriched in cell cycle and cell survival pathways. This suggests CD123 may serve as a biomarker for chemoresistance, but not stemness of AML cells. We further investigated the role of epigenetic factors in regulating the survival of chemoresistant leukemia cells. Epigenetic drugs, especially histone deacetylase inhibitors (HDACis), effectively induced apoptosis of chemoresistant cells. Furthermore, HDACi Romidepsin largely reversed gene expression profile of resistant cells and efficiently targeted and removed chemoresistant leukemia blasts in xenograft AML mouse model. More interestingly, Romidepsin preferentially targets CD123+ cells, while chemotherapy drug Ara-C mainly targeted fast-growing, CD123− cells. Therefore, Romidepsin alone or in combination with Ara-C may be a potential treatment strategy for chemoresistant patients.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Robak T, Wierzbowska A. Current and emerging therapies for acute myeloid leukemia. Clin Ther. 2009;31(Pt 2):2349–70.
Maugeri-Sacca M, Vici P, Di Lauro L, Barba M, Amoreo CA, Gallo E, et al. Cancer stem cells: are they responsible for treatment failure? Future Oncol. 2014;10:2033–44.
Colak S, Medema JP. Cancer stem cells--important players in tumor therapy resistance. FEBS J. 2014;281:4779–91.
Adorno-Cruz V, Kibria G, Liu X, Doherty M, Junk DJ, Guan D, et al. Cancer stem cells: targeting the roots of cancer, seeds of metastasis, and sources of therapy resistance. Cancer Res. 2015;75:924–9.
Crea F, Danesi R, Farrar WL. Cancer stem cell epigenetics and chemoresistance. Epigenomics. 2009;1:63–79.
Horton SJ, Huntly BJ. Recent advances in acute myeloid leukemia stem cell biology. Haematologica. 2012;97:966–74.
Knoechel B, Roderick JE, Williamson KE, Zhu J, Lohr JG, Cotton MJ, et al. An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia. Nat Genet. 2014;46:364–70.
Easwaran H, Tsai HC, Baylin SB. Cancer epigenetics: tumor heterogeneity, plasticity of stem-like states, and drug resistance. Mol Cell. 2014;54:716–27.
Dawson MA, Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell. 2012;150:12–27.
Ropero S, Esteller M. The role of histone deacetylases (HDACs) in human cancer. Mol Oncol. 2007;1:19–25.
Humeniuk R, Mishra PJ, Bertino JR, Banerjee D. Molecular targets for epigenetic therapy of cancer. Curr Pharm Biotechnol. 2009;10:161–5.
Glasspool RM, Teodoridis JM, Brown R. Epigenetics as a mechanism driving polygenic clinical drug resistance. Br J Cancer. 2006;94:1087–92.
Baylin SB. Resistance, epigenetics and the cancer ecosystem. Nat Med. 2011;17:288–9.
van Vlerken LE, Hurt EM, Hollingsworth RE. The role of epigenetic regulation in stem cell and cancer biology. J Mol Med (Berl). 2012;90:791–801.
Hernandez-Vargas H, Sincic N, Ouzounova M, Herceg Z. Epigenetic signatures in stem cells and cancer stem cells. Epigenomics. 2009;1:261–80.
Toh TB, Lim JJ, Chow EK. Epigenetics in cancer stem cells. Mol Cancer. 2017;16:29
Shukla S, Meeran SM. Epigenetics of cancer stem cells: pathways and therapeutics. Biochim Biophys Acta. 2014;1840:3494–502.
Muñoz P, Iliou MS, Esteller M. Epigenetic alterations involved in cancer stem cell reprogramming. Mol Oncol. 2012;6:620–36.
Brenner AK, Reikvam H, Rye KP, Hagen KM, Lavecchia A, Bruserud O. CDC25 inhibition in acute myeloid leukemia-a study of patient heterogeneity and the effects of different inhibitors. Molecules. 2017;22:E446.
Pabst C, Krosl J, Fares I, Boucher G, Ruel R, Marinier A, et al. Identification of small molecules that support human leukemia stem cell activity ex vivo. Nat Methods. 2014;11:436–42.
Negoro E, Yamauchi T, Urasaki Y, Nishi R, Hori H, Ueda T. Characterization of cytarabine-resistant leukemic cell lines established from five different blood cell lineages using gene expression and proteomic analyses. Int J Oncol. 2011;38:911–9.
Patro R, Duggal G, Love MI, Irizarry RA, Kingsford C. Salmon provides fast and bias-aware quantification of transcript expression. Nat Methods. 2017;14:417–9.
Soneson C, Love MI, Robinson MD. Differential analyses for RNA-seq: transcript-level estimates improve gene-level inferences. F1000Res. 2015;4:1521.
Kamburov A, Wierling C, Lehrach H, Herwig R. ConsensusPathDB--a database for integrating human functional interaction networks. Nucleic Acids Res. 2009;37(Database issue):D623–8.
Kamburov A, Pentchev K, Galicka H, Wierling C, Lehrach H, Herwig R. ConsensusPathDB: toward a more complete picture of cell biology. Nucleic Acids Res. 2011;39(Database issue):D712–7.
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545–50.
Chou TC. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 2010;70:440–6.
Vergez F, Green AS, Tamburini J, Sarry JE, Gaillard B, Cornillet-Lefebvre P, et al. High levels of CD34+CD38low/-CD123+ blasts are predictive of an adverse outcome in acute myeloid leukemia: a Groupe Ouest-Est des Leucemies Aigues et Maladies du Sang (GOELAMS) study. Haematologica. 2011;96:1792–8.
McDermott M, Eustace AJ, Busschots S, Breen L, Crown J, Clynes M, et al. In vitro development of chemotherapy and targeted therapy drug-resistant cancer cell lines: a practical guide with case studies. Front Oncol. 2014;4:40.
Ding Y, Gao H, Zhang Q. The biomarkers of leukemia stem cells in acute myeloid leukemia. Stem Cell Investig. 2017;4:19.
Mony U, Jawad M, Seedhouse C, Russell N, Pallis M. Resistance to FLT3 inhibition in an in vitro model of primary AML cells with a stem cell phenotype in a defined microenvironment. Leukemia. 2008;22:1395–401.
Anaya J. OncoLnc: linking TCGA survival data to mRNAs, miRNAs, and lncRNAs. PeerJ Comput Sci. 2016;2:e67.
Ng SW, Mitchell A, Kennedy JA, Chen WC, McLeod J, Ibrahimova N, et al. A 17-gene stemness score for rapid determination of risk in acute leukaemia. Nature. 2016;540:433–7.
Wang Y, Cardenas H, Fang F, Condello S, Taverna P, Segar M, et al. Epigenetic targeting of ovarian cancer stem cells. Cancer Res. 2014;74:4922–36.
Sikandar S, Dizon D, Shen X, Li Z, Besterman J, Lipkin SM. The class I HDAC inhibitor MGCD0103 induces cell cycle arrest and apoptosis in colon cancer initiating cells by upregulating Dickkopf-1 and non-canonical Wnt signaling. Oncotarget. 2010;1:596–605.
Bhatla T, Wang J, Morrison DJ, Raetz EA, Burke MJ, Brown P, et al. Epigenetic reprogramming reverses the relapse-specific gene expression signature and restores chemosensitivity in childhood B-lymphoblastic leukemia. Blood. 2012;119:5201–10.
Kreso A, Dick JE. Evolution of the cancer stem cell model. Cell Stem Cell. 2014;14:275–91.
Witt AE, Lee CW, Lee TI, Azzam DJ, Wang B, Caslini C, et al. Identification of a cancer stem cell-specific function for the histone deacetylases, HDAC1 and HDAC7, in breast and ovarian cancer. Oncogene. 2017;36:1707–20.
Zhou J, Bi C, Cheong LL, Mahara S, Liu SC, Tay KG, et al. The histone methyltransferase inhibitor, DZNep, up-regulates TXNIP, increases ROS production, and targets leukemia cells in AML. Blood. 2011;118:2830–9.
Kreso A, van Galen P, Pedley NM, Lima-Fernandes E, Frelin C, Davis T, et al. Self-renewal as a therapeutic target in human colorectal cancer. Nat Med. 2014;20:29–36.
Fiskus W, Sharma S, Qi J, Shah B, Devaraj SG, Leveque C, et al. BET protein antagonist JQ1 is synergistically lethal with FLT3 tyrosine kinase inhibitor (TKI) and overcomes resistance to FLT3-TKI in AML cells expressing FLT-ITD. Mol Cancer Ther. 2014;13:2315–27.
Ashihara E, Takada T, Maekawa T. Targeting the canonical Wnt/β-catenin pathway in hematological malignancies. Cancer Sci. 2015;106:665–71.
Fauriat C, Olive D. AML drug resistance: c-Myc comes into play. Blood. 2014;123:3528–30.
Nanbakhsh A, Pochon C, Mallavialle A, Amsellem S, Bourhis JH, Chouaib S. c-Myc regulates expression of NKG2D ligands ULBP1/2/3 in AML and modulates their susceptibility to NK-mediated lysis. Blood. 2014;123:3585–95.
Göllner S, Oellerich T, Agrawal-Singh S, Schenk T, Klein HU, Rohde C, et al. Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia. Nat Med. 2017;23:69–78. 01
Eldin TK, Abdelsalam EMN, Razek GA, Nafady H, Saleh MFM. Diagnostic and prognostic value of CD123 in acute myeloid leukemia (AML). Clin Lymphoma Myeloma Leuk. 2017;17 Suppl. 2:S272–3.
Al-Mawali A, Pinto AD, Al-Zadjali S. CD34+CD38-CD123+ cells are present in virtually all acute myeloid leukaemia blasts: a promising single unique phenotype for minimal residual disease detection. Acta Haematol. 2017;138:175–81.
Al-Mawali A, Gillis D, Lewis I. Immunoprofiling of leukemic stem cells CD34+/CD38-/CD123+ delineate FLT3/ITD-positive clones. J Hematol Oncol. 2016;9:61.
Pietsch EC, Dong J, Cardoso R, Zhang X, Chin D, Hawkins R, et al. Anti-leukemic activity and tolerability of anti-human CD47 monoclonal antibodies. Blood Cancer J. 2017;7:e536.
Lee TK, Cheung VC, Lu P, Lau EY, Ma S, Tang KH, et al. Blockade of CD47-mediated cathepsin S/protease-activated receptor 2 signaling provides a therapeutic target for hepatocellular carcinoma. Hepatology. 2014;60:179–91.
Acknowledgements
pMSCV-GFP-Luc plasmid is a kind gift of Dr. Lizi Wu at the University of Florida. AML patient samples are provided by Dr. Leylah Drusbosky from the University of Florida. JQ1 is a kind gift from Dr. J. Brandner from the Dana-Farber Cancer Institute. We thank Dr. Chengguo Xing from the University of Florida for the essential reagents.
Author contributions
BY, QC and KS performed experiments and contributed to experimental design. BY, MT, HL and AG contributed to the data analysis. JDK characterized and provided leukemic patient samples. BX, SH and YQ planned the research strategy and wrote the manuscript.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Yan, B., Chen, Q., Shimada, K. et al. Histone deacetylase inhibitor targets CD123/CD47-positive cells and reverse chemoresistance phenotype in acute myeloid leukemia. Leukemia 33, 931–944 (2019). https://doi.org/10.1038/s41375-018-0279-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41375-018-0279-6
This article is cited by
-
Combined inhibition of BCL-2 and MCL-1 overcomes BAX deficiency-mediated resistance of TP53-mutant acute myeloid leukemia to individual BH3 mimetics
Blood Cancer Journal (2023)
-
Therapeutic nucleus-access BNCT drug combined CD47-targeting gene editing in glioblastoma
Journal of Nanobiotechnology (2022)
-
Nrf2 overexpression increases the resistance of acute myeloid leukemia to cytarabine by inhibiting replication factor C4
Cancer Gene Therapy (2022)
-
Inhibition of EZH2 by chidamide exerts antileukemia activity and increases chemosensitivity through Smo/Gli-1 pathway in acute myeloid leukemia
Journal of Translational Medicine (2021)
-
SIRPα-αCD123 fusion antibodies targeting CD123 in conjunction with CD47 blockade enhance the clearance of AML-initiating cells
Journal of Hematology & Oncology (2021)