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

SummaryImatinib mesylate (IM) induces remission in chronic myelogenous leukemia (CML) patients but does not eliminate leukemia stem cells (LSCs), which remain a potential source of relapse. Here we investigated the ability of HDAC inhibitors (HDACis) to target CML stem cells. Treatment with HDACis 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 HDACis with IM markedly diminished LSCs in a transgenic mouse model of CML. The interaction of IM and HDACis inhibited genes regulating hematopoietic stem cell maintenance and survival. HDACi treatment represents an effective strategy to target LSCs in CML patients receiving tyrosine kinase inhibitors.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (227 K)Download as PowerPoint slideHighlights► CML results from hematopoietic stem cell transformation by the BCR-ABL gene ► The BCR-ABL inhibitor imatinib (IM) fails to eliminate leukemia stem cells (LSC) ► HDAC inhibitors (HDACi) combined with IM induced apoptosis in quiescent CML LSCs ► In vivo administration of HDACi with IM-depleted LSCs in a CML mouse model