Inhibition of novel GCN5-ATM axis restricts the onset of acquired drug resistance in leukemia

Int J Cancer. 2018 May 15;142(10):2175-2185. doi: 10.1002/ijc.31242. Epub 2018 Jan 13.


Leukemia is majorly treated by topoisomerase inhibitors that induce DNA double strand breaks (DSB) resulting in cell death. Consequently, modulation of DSB repair pathway renders leukemic cells resistant to therapy. As we do not fully understand the regulation of DSB repair acquired by resistant cells, targeting these cells has been a challenge. Here we investigated the regulation of DSB repair pathway in early drug resistant population (EDRP) and late drug resistant population (LDRP). We found that doxorubicin induced equal DSBs in parent and EDRP cells; however, cell death is induced only in the parent cells. Further analysis revealed that EDRP cells acquire relaxed chromatin via upregulation of lysine acetyl transferase KAT2A (GCN5). Drug treatment induces GCN5 interaction with ATM facilitating its recruitment to DSB sites. Hyperactivated ATM maximize H2AX, NBS1, BRCA1, Chk2, and Mcl-1 activation, accelerating DNA repair and survival of EDRP cells. Consequently, inhibition of GCN5 significantly reduces ATM activation and survival of EDRP cells. Contrary to EDRP, doxorubicin failed to induce DSBs in LDRP because of reduced drug uptake and downregulation of TOP2β. Accordingly, ATM inhibition prior to doxorubicin treatment completely eliminated EDRP but not LDRP. Furthermore, baseline AML samples (n = 44) showed significantly higher GCN5 at mRNA and protein levels in MRD positive compared to MRD negative samples. Additionally, meta-analysis (n = 221) showed high GCN5 expression correlates with poor overall survival. Together, these results provide important insights into the molecular mechanism specific to EDRP and will have implications for the development of novel therapeutics for AML.

Keywords: ATM; DNA repair; GCN5; chemoresistance; leukemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors*
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • DNA Damage
  • DNA Repair
  • Doxorubicin / pharmacology
  • Drug Resistance, Neoplasm
  • HEK293 Cells
  • HL-60 Cells
  • Humans
  • K562 Cells
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / enzymology
  • Leukemia, Myeloid, Acute / genetics
  • Signal Transduction
  • THP-1 Cells
  • p300-CBP Transcription Factors / antagonists & inhibitors*
  • p300-CBP Transcription Factors / genetics
  • p300-CBP Transcription Factors / metabolism


  • Doxorubicin
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins