HDAC1,2 Knock-Out and HDACi Induced Cell Apoptosis in Imatinib-Resistant K562 Cells.

Shu-Huey Chen,Jyh-Ming Chow,Kai-Wen Hsu,Yao-Yu Hsieh,Wen-Shyang Hsieh,Wei-Ming Chi,Beished M Shabangu,Chun-Yu Lin,Chia-Hwa Lee

doi:10.3390/ijms20092271

Abstract

Since imatinib (Glivec or Gleevec) has been used to target the BCR-ABL fusion protein, chronic myeloid leukemia (CML) has become a manageable chronic disease with long-term survival. However, 15%–20% of CML patients ultimately develop resistance to imatinib and then progress to an accelerated phase and eventually to a blast crisis, limiting treatment options and resulting in a poor survival rate. Thus, we investigated whether histone deacetylase inhibitors (HDACis) could be used as a potential anticancer therapy for imatinib-resistant CML (IR-CML) patients. By applying a noninvasive apoptosis detection sensor (NIADS), we found that panobinostat significantly enhanced cell apoptosis in K562 cells. A further investigation showed that panobinostat induced apoptosis in both K562 and imatinib-resistant K562 (IR-K562) cells mainly via H3 and H4 histone acetylation, whereas panobinostat targeted cancer stem cells (CSCs) in IR-K562 cells. Using CRISPR/Cas9 genomic editing, we found that HDAC1 and HDAC2 knockout cells significantly induced cell apoptosis, indicating that the regulation of HDAC1 and HDAC2 is extremely important in maintaining K562 cell survival. All information in this study indicates that regulating HDAC activity provides therapeutic benefits against CML and IR-CML in the clinic.

Highlights

Chronic myeloid leukemia (CML) is a hematological disease with reciprocal translocation between the break-point cluster (BCR) gene on chromosome 22 and the Abelson leukemia virus oncogene (ABL) gene on chromosome 9, termed the Philadelphia (Ph) chromosome
Microarray analyses showed that histone deacetylase inhibitors (HDACis) manipulate genes in several biofunctional classes, such as cell cycle inhibition [19], β-catenin-related signaling, lineage-specific differentiation [20] and apoptotic-related cell death
Previous studies have shown that HDACis transcriptionally activated p21 promoter-associated histones by either acetylation or methylation, whereas these factors were not altered in a multiple myeloma cell line [21]

Summary

Introduction

Chronic myeloid leukemia (CML) is a hematological disease with reciprocal translocation between the break-point cluster (BCR) gene on chromosome 22 and the Abelson leukemia virus oncogene (ABL) gene on chromosome 9, termed the Philadelphia (Ph) chromosome. With the discovery of effective tyrosine kinase inhibitors (TKIs), such as imatinib (Glivec or Gleevec) and its derivatives dasatinib, nilotinib, bosutinib, and ponatinib, CML has become a manageable chronic disease with a long-term survival exceeding 85% [2]. In the clinic, imatinib resistance has become a major problem for CML treatment, mainly as a consequence of BCR-ABL mutations, BCR-ABL overexpression and other BCR-ABL-independent pathways. Approximately 15%–20% of these CML patients develop resistance to imatinib and progress to an accelerated phase and eventually to a blast crisis [3]. Overcoming imatinib resistance has attracted increased attention during the treatment of CML

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Results

Conclusion