Molecular and biologic characterization and drug sensitivity of pan-histone deacetylase inhibitor resistant acute myeloid leukemia cells

Warren Fiskus, Rekha Rao, Pravina Fernandez, Bryan Herger, Yonghua Yang, Jianguang Chen, Ravindra Kolhe, Aditya Mandawat, Yongchao Wang, Rajeshree Joshi, Kelly Eaton, Pearl Lee, Peter Atadja, Stephen Peiper, Kapil Bhalla

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

Hydroxamic acid analog pan-histone deacetylase (HDAC) inhibitors (HA-HDIs) have shown preclinical and clinical activity against human acute leukemia. Here we describe HA-HDI-resistant human acute myeloid leukemia (AML) HL-60 (HL-60/LR) cells that are resistant to LAQ824, vorinostat, LBH589, and sodium butyrate. HL-60/LR cells show increased expression of HDACs 1, 2, and 4 but lack HDAC6 expression, with concomitant hyperacetylation of heat shock protein 90 (hsp90). Treatment with HA-HDI failed to further augment hsp90 acetylation, or increase the levels of p21 or reactive oxygen species (ROSs), in HL-60/LR versus HL-60 cells. Although cross-resistant to antileukemia agents (eg, cytarabine, etoposide, and TRAIL), HL-60/LR cells are collaterally sensitive to the hsp90 inhibitor 17-AAG. Treatment with 17-AAG did not induce hsp70 or deplete the hsp90 client proteins AKT and c-Raf. HL-60/LR versus HL-60 cells display a higher growth fraction and shorter doubling time, along with a shorter interval to generation of leukemia and survival in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Thus, resistance of AML cells to HA-HDIs is associated with loss of HDAC6, hyperacetylation of hsp90, aggressive leukemia phenotype, and collateral sensitivity to 17-AAG. These findings suggest that an hsp90 inhibitor-based antileukemia therapy may override de novo or acquired resistance of AML cells to HA-HDIs.

Original languageEnglish (US)
Pages (from-to)2896-2905
Number of pages10
JournalBlood
Volume112
Issue number7
DOIs
StatePublished - Oct 1 2008

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Fingerprint Dive into the research topics of 'Molecular and biologic characterization and drug sensitivity of pan-histone deacetylase inhibitor resistant acute myeloid leukemia cells'. Together they form a unique fingerprint.

  • Cite this

    Fiskus, W., Rao, R., Fernandez, P., Herger, B., Yang, Y., Chen, J., Kolhe, R., Mandawat, A., Wang, Y., Joshi, R., Eaton, K., Lee, P., Atadja, P., Peiper, S., & Bhalla, K. (2008). Molecular and biologic characterization and drug sensitivity of pan-histone deacetylase inhibitor resistant acute myeloid leukemia cells. Blood, 112(7), 2896-2905. https://doi.org/10.1182/blood-2007-10-116319