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Blood, 1 October 2008, Vol. 112, No. 7, pp. 2896-2905.
Prepublished online as a Blood First Edition Paper on July 25, 2008; DOI 10.1182/blood-2007-10-116319.
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Submitted October 18, 2007
Accepted July 5, 2008
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, and Kapil Bhalla*
MCG Cancer Center, Medical College of Georgia, Augusta, GA, United States
Novartis, Novartis Institute for Biomedical Research, Inc., Cambridge, MA, United States
* Corresponding author; email: kbhalla{at}mcg.edu.
Hydroxamic acid analogue pan-histone deacetylase (HDAC) inhibitors (HA-HDIs) have shown preclinical and clinical activity against human acute leukemia. Here we describe HA-HDI resistant human 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 (hsp) 90. Treatment with HA-HDI failed to further augment hsp90 acetylation, or increase the levels of p21 or reactive oxygen species (ROS), in HL-60/LR versus HL-60 cells. Although cross-resistant to anti-leukemia agents, e.g., 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 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 anti-leukemia therapy may override de novo or acquired resistance of AML cells to HA-HDIs.
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