Oncotarget

Research Papers:

Establishment and characterization of hypomethylating agent-resistant cell lines, MOLM/AZA-1 and MOLM/DEC-5

Eun-Hye Hur _, Seung-Hyun Jung, Bon-Kwan Goo, Juhyun Moon, Yunsuk Choi, Dae Ro Choi, Yeun-Jun Chung and Je-Hwan Lee

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Oncotarget. 2017; 8:11748-11762. https://doi.org/10.18632/oncotarget.14342

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Abstract

Eun-Hye Hur1,*, Seung-Hyun Jung2,3,*, Bon-Kwan Goo1, Juhyun Moon1, Yunsuk Choi4, Dae Ro Choi5, Yeun-Jun Chung3,6, Je-Hwan Lee1

1Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

2Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea

3Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea

4Division of Hematology and Hematological Malignancies, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea

5Division of Hemato-Oncology, Hallym University Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon, Korea

6Department of Microbiology, College of Medicine, The Catholic University of Korea

*These authors have contributed equally to this work

Correspondence to:

Je-Hwan Lee, email: [email protected]

Yeun-Jun Chung, email: [email protected]

Keywords: azacitidine, decitabine, MOLM-13, resistance, cytogenetics

Received: June 16, 2016    Accepted: December 05, 2016    Published: December 28, 2016

ABSTRACT

Two hypomethylating agents (HMAs), azacitidine and decitabine, have demonstrated clinical activities in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML); however, potential problems include development of acquired resistance. HMA-resistant patients have very poor prognosis and this cohort of patients constitutes an important area of research. To understand the mechanisms underlying HMA-resistance and to overcome it, we established an azacitidine-resistant cell line, MOLM/AZA-1 and a decitabine-resistant cell line, MOLM/DEC-5 using MOLM-13. For cytogenetic characterization, we performed microarray-based comparative genomic hybridization (array-CGH), which identified a total of 15 copy number alterations (CNAs). Among these CNAs, eight regions in HMA-resistant cell lines showed CNA patterns distinct from the parental MOLM-13 genome. Single nucleotide polymorphism (SNP) microarray was also performed to obtain a more reliable interpretation of the identified CNAs, and all HMA-resistance-specific CNAs except one detected by array-CGH were successfully validated. In addition to CNAs, copy neutral loss of heterozygosity and mosaic loss events were identified in HMA-resistant cell lines. In our resistant cell lines, MDR-1 was not overexpressed, while DNMT3b was upregulated. Azacitidine and decitabine did not inhibit DNMT1, DNMT3a, or DNMT3b in both HMA-resistant cell lines, while they inhibited the enzymes in parental MOLM-13. We also developed mouse xenograft models using MOLM/AZA-1 and MOLM/DEC-5. Our in vitro and in vivo models of HMA-resistant cell lines will provide clues for the elucidation of molecular mechanisms related to the development of resistance to HMA and tools for the application of novel therapeutics for AML and MDS.


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