Steven Grant, MD
Dr. Grant indicated no relevant conflicts of interest.
Zhang B, Strauss AC, Chu S, et al. Effective targeting of quiescent chronic myelogenous leukemia stem cells by histone deacetylase inhibitors in combination with imatinib mesylate. Cancer Cell. 2010;17:427-442.
Histone deacetylase inhibitors (HDACIs) are commonly grouped, along with the prototypical Bcr/abl kinase inhibitor imatinib mesylate, as representative targeted agents. However, HDACIs are truly chameleon-like molecules, which, in addition to modifying chromatin structure, and, by extension, gene expression, trigger acetylation of diverse proteins, including chaperone and DNA repair proteins, as well transcription factors, among numerous others. Given their pleiotropic actions, HDACIs have proven to be very effective, at least in the preclinical setting, in potentiating the activity of not only standard cytotoxic agents, but also other targeted signal transduction inhibitors. For example, multiple groups have reported that HDACIs, and particularly pan-HDACIs, potentiate the anti-leukemic effects of imatinib and other Bcr/abl kinase inhibitors in CML cells through a variety of mechanisms, including enhancing inactivation of Bcr/abl.1,2
Aside from the issue of the emergence or pre-existence of Bcr/abl kinase inhibitor resistance, a major theoretical barrier to curative approaches to CML is the possibility that such agents may be incapable of eradicating CML stem or leukemia-initiating cells. Indeed, preclinical evidence suggests that Bcr/ abl kinase inhibitors are relatively ineffective in killing cytokinetically quiescent CML stem cells.3 Assuming failure to eradicate such stems cells represents a legitimate clinical issue, the question then remains whether addition of an HDACI would help to overcome this problem.
Zhang et al. from the Bhatia laboratory at City of Hope National Medical Center in California addressed this question directly for the first time. They reported that co-treatment with imatinib and the pan-HDACI LBH-589 effectively induced apoptosis in non-proliferating, otherwise imatinib-resistant CML progenitor cells and significantly reduced their capacity to repopulate the marrows of immunodeficient mice. Importantly, co-administration of HDACIs with imatinib proved very potent in reducing the number of putative CML stem cells in a transgenic mouse model of CML. The authors conclude that if the results of this study can be extrapolated to humans with CML such that residual LSCs can be reduced, HDACIs might enhance the ability of patients to maintain long-term remissions following discontinuation of Bcr/abl kinase inhibitor treatment.
This provocative study raises several important questions. For instance, the mechanism(s) by which HDACIs promote imatinib-mediated lethality in primitive progenitors remain(s) to be defined. It is possible that these interactions reflect further down-regulation/inactivation of Bcr/abl and/or the contribution of other HDACI-associated genetic changes. It will also be important to determine whether similar interactions occur with second-generation Bcr/abl kinase inhibitors or in the setting of imatinib-conferring mutations. Finally, the impact of eradicating CML stem cells remains to be determined. Whatever the answers to these questions, the present findings provide a theoretical foundation for future efforts to define the contribution of HDACIs to the treatment of CML and possibly other hematologic malignancies in which stem cells have been postulated to play a significant role.
- Yu C, Rahmani M, Almenara J, et al. Histone deacetylase inhibitors promote STI571-mediated apoptosis in STI571-sensitive and -resistant Bcr/ Abl+ human myeloid leukemia cells. Cancer Res. 2003;63:2118-2126.
- Fiskus W, Pranpat M, Balasis M, et al. Cotreatment with vorinostat (suberoylanilide hydroxamic acid) enhances activity of dasatinib (BMS-354825) against imatinib mesylate–sensitive or imatinib mesylate–resistant chronic myelogenous leukemia cells. Clin Cancer Res. 2006;12:5869-5878.
- Copland M, Hamilton A, Elrick LJ, et al. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood. 2006;107:4532-4539.
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