Effective Targeting of Quiescent Chronic Myelogenous Leukemia Stem Cells by Histone Deacetylase Inhibitors in Combination with Imatinib Mesylate

Abstract

Summary Imatinib mesylate (IM) induces remission in chronic myelogenous leukemia (CML) patients but does not eliminate leukemia stem cells (LSC), which remain a potential source of relapse. Here we investigated the ability of HDAC inhibitors (HDACi) to target CML stem cells. Treatment with HDACi combined with IM effectively induced apoptosis in quiescent CML progenitors resistant to elimination by IM alone, and eliminated CML stem cells capable of engrafting immunodeficient mice. In vivo administration of HDACi with IM markedly diminished LSC in a transgenic mouse model of CML. The interaction of IM and HDACi inhibited genes regulating hematopoietic stem cell maintenance and survival. HDACi treatment represents an effective strategy to target LSC in CML patients receiving tyrosine kinase inhibitors.

Acetylation controls Notch3 stability and function in T-cell leukemia

“…Acetylation/deacetylation balance has been recently suggested to have a role in the development and progression of T-cell acute lymphoblastic leukemia (T-ALL), a very aggressive disease, which accounts for 10-15% of pediatric and 25% of adult ALL cases. Indeed, HDAC inhibitors (HDACi) have been recently shown to display anti-tumor activity upon glucocorticoid resistant T-ALL cell lines and patientderived blasts, confirming therapeutic efficacy observed in other tumors (for example, B-cell acute lymphoblastic leukemia, chronic myeloid leukemia and a number of solid tumors) (Tsapis et al, 2007;Zhang et al, 2010).…”

Insights into the stem cells of chronic myeloid leukemia

“…126 Another report has suggested that combining histone deacetylase inhibitors (for example, LAQ824) with IM may be more effective in targeting quiescent CML stem cells than IM alone by inhibiting several genes important to the regulation of HSC maintenance and survival. 26 More recently, evidence has been found to suggest that targeting autophagy, a process that allows cells to adapt to environmental stresses, might also allow CML stem and progenitor cells to be effectively targeted. 127 Other potential strategies include induction of protein phosphatase-2A activation by FTY720 128,129 and exposure of CML stem cells to the farnesyltransferase inhibitor (BMS-214662).…”

“…19,[22][23][24] These discoveries have, in turn, reactivated a search for newer agents that can be shown to kill CML stem cells. 25,26 In addition, they have highlighted the need for better models of the human disease that will allow a more accurate prediction of the clinical utility of newer agents.…”

WZ4002, a third-generation EGFR inhibitor, can overcome anoikis resistance in EGFR-mutant lung adenocarcinomas more efficiently than Src inhibitors

“…11,12 Also, Abl TKIs for chronic myelogenous leukemia (CML) with the Bcr-Abl oncogene are not able to eradicate tumor cells, but histone deacetylase (HDAC) inhibitors can eliminate CML stem cells in combination with the Abl TKI, imatinib. 13 This indicates that a subset of tumor cells can survive treatment with molecularly targeted drugs against the addicting oncogene product through various genetic and/or epigenetic mechanisms. These observations led us to surmise that a subpopulation of lung adenocarcinoma cells in suspension should survive the combination therapy with a Src TKI and ABT-263, but may not last with a combination treatment of a Src TKI, a Bcl-2 inhibitor, and an HDAC inhibitor.…”