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Depletion of ?-catenin by Histone Deacetylase Inhibition Confers Elimination of CML Stem Cells in Combination with Imatinib.

ABSTRACT: Quiescent leukemia stem cells (LSCs) that are insensitive to BCR-ABL tyrosine kinase inhibitors confer resistance to imatinib in chronic myelogenous leukemia (CML). Identifying proteins to regulate survival and stemness of LSCs is urgently needed. Although histone deacetylase inhibitors (HDACis) can eliminate quiescent LSCs in CML, little is known about the underlying mechanism that HDACis kill LSCs. By fishing with a biotin-labeled probe, we identified that HDACi JSL-1 bound to the protein ?-catenin. ?-Catenin expression was higher in LSCs from CML patients than normal hematopoietic stem cells. Silencing ?-catenin in human CML CD34(+) bone-marrow (BM) cells sufficiently eliminated LSCs, which suggests that ?-catenin is required for survival of CML LSCs. Pharmacological inhibition of ?-catenin thwarted survival and self-renewal of human CML CD34(+) cells in vitro, and of murine LSCs in BCR-ABL-driven CML mice. ?-Catenin inhibition reduced long-term engraftment of human CML CD34(+) cells in NOD.Cg-Prkdc (scid) II2rg (tm1Sug)/JicCrl (NOG) mice. Silencing ?-catenin by shRNA in human primary CD34(+) cells did not alter ?-catenin, implying a ?-catenin-independent role of ?-catenin in survival and self-renewal of CML LSCs. Taken together, our findings validate that ?-catenin may be a novel therapeutic target of LSCs, and suppression of ?-catenin by HDACi may explain elimination of CML LSCs.

SUBMITTER: Jin Y

PROVIDER: S-EPMC4997248 | biostudies-other | 2016

REPOSITORIES: biostudies-other

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Depletion of γ-catenin by Histone Deacetylase Inhibition Confers Elimination of CML Stem Cells in Combination with Imatinib.

Jin Yanli Y Yao Yiwu Y Chen Li L Zhu Xiaohui X Jin Bei B Shen Yingying Y Li Juan J Du Xin X Lu Yuhong Y Jiang Sheng S Pan Jingxuan J

Theranostics 20160812 11

Quiescent leukemia stem cells (LSCs) that are insensitive to BCR-ABL tyrosine kinase inhibitors confer resistance to imatinib in chronic myelogenous leukemia (CML). Identifying proteins to regulate survival and stemness of LSCs is urgently needed. Although histone deacetylase inhibitors (HDACis) can eliminate quiescent LSCs in CML, little is known about the underlying mechanism that HDACis kill LSCs. By fishing with a biotin-labeled probe, we identified that HDACi JSL-1 bound to the protein γ-ca ...[more]

PMID: 27570562

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Project description: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 a novel and effective strategy to target LSC in CML patients receiving tyrosine kinase inhibitors. CML CD34+CD38- cells were selected using flow cytometry sorting and treated with IM, LBH and the combination of IM and LBH or cultured without exposure to drugs (controls) for 24 hours (n=3 each). Total RNA from 5000 cells was extracted using the RNeasy kit (Qiagen), amplified and labeled using GeneChip Two-Cycle Target Labeling and Control Reagents (Affymetrix, Santa Clara, CA). 15 Âµg cRNA from each sample was hybridized to Affymetrix GeneChip Human Genome U133 Plus 2.0 Arrays. Microarray data analyses were performed using R (version 2.9) with genomic analysis packages from Bioconductor (version 2.4). Expression data were normalized using the robust multiarray average (RMA) algorithm, with background adjustment, quantile normalization and median polish summarization. Probesets with low expression levels or low variability across samples were filtered. For genes with multiple probesets, the gene level expression was set to be the median of the probesets. Linear regression was used to model the gene expression with the consideration of 2x2 factorial design and matched samples. Differentially expressed genes were identified by calculating empirical Bayes moderated t-statistic, and p-values were adjusted by FDR using the âLIMMAâ package. Gene Set Enrichment Analyses (GSEA) was performed using GSEA software version 2.04 [http://www.broadinstitute.org/gsea/] to detect enrichment of predetermined gene sets using t-scores and gene sets in C2 (curated gene sets) category from the Molecular Signature Database (MsigDB). Gene sets representing common functional categories were categorized and grouped. We also analyzed enrichment of gene sets with common transcription factor binding sites (586 sets) from MsigDB.

Dataset Information

Depletion of ?-catenin by Histone Deacetylase Inhibition Confers Elimination of CML Stem Cells in Combination with Imatinib.

Publications

Depletion of γ-catenin by Histone Deacetylase Inhibition Confers Elimination of CML Stem Cells in Combination with Imatinib.

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