Dataset Information

Genetic and pharmacologic inhibition of ?-catenin targets imatinib-resistant leukemia stem cells in CML.

ABSTRACT: A key characteristic of hematopoietic stem cells (HSCs) is the ability to self-renew. Genetic deletion of ?-catenin during fetal HSC development leads to impairment of self-renewal while ?-catenin is dispensable in fully developed adult HSCs. Whether ?-catenin is required for maintenance of fully developed CML leukemia stem cells (LSCs) is unknown. Here, we use a conditional mouse model to show that deletion of ?-catenin after CML initiation does not lead to a significant increase in survival. However, deletion of ?-catenin synergizes with imatinib (IM) to delay disease recurrence after imatinib discontinuation and to abrogate CML stem cells. These effects can be mimicked by pharmacologic inhibition of ?-catenin via modulation of prostaglandin signaling. Treatment with the cyclooxygenase inhibitor indomethacin reduces ?-catenin levels and leads to a reduction in LSCs. In conclusion, inhibiting ?-catenin by genetic inactivation or pharmacologic modulation is an effective combination therapy with imatinib and targets CML stem cells.

SUBMITTER: Heidel FH

PROVIDER: S-EPMC3339412 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Genetic and pharmacologic inhibition of β-catenin targets imatinib-resistant leukemia stem cells in CML.

Heidel Florian H FH Bullinger Lars L Feng Zhaohui Z Wang Zhu Z Neff Tobias A TA Stein Lauren L Kalaitzidis Demetrios D Lane Steven W SW Armstrong Scott A SA

Cell stem cell 20120401 4

A key characteristic of hematopoietic stem cells (HSCs) is the ability to self-renew. Genetic deletion of β-catenin during fetal HSC development leads to impairment of self-renewal while β-catenin is dispensable in fully developed adult HSCs. Whether β-catenin is required for maintenance of fully developed CML leukemia stem cells (LSCs) is unknown. Here, we use a conditional mouse model to show that deletion of β-catenin after CML initiation does not lead to a significant increase in survival. H ...[more]

PMID: 22482506

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Project description:Despite the success of imatinib and other tyrosine kinase inhibitors (TKIs), chronic myeloid leukemia (CML) remains largely incurable, and a number of CML patients die due to Abl mutation-related drug resistance and blast crisis. The aim of this study was to evaluate proliferation inhibition and apoptosis induction by down-regulating PPP2R5C gene expression in the imatinib-sensitive and imatinib-resistant CML cell lines K562, K562R (imatinib resistant without an Abl gene mutation), 32D-Bcr-Abl WT (imatinib-sensitive murine CML cell line with a wild type Abl gene) and 32D-Bcr-Abl T315I (imatinib resistant with a T315I Abl gene mutation) and primary cells from CML patients by RNA interference. PPP2R5C siRNAs numbered 799 and 991 were obtained by chemosynthesis. Non-silencing siRNA scrambled control (SC)-treated, mock-transfected, and untreated cells were used as controls. The PPP2R5C mRNA and protein expression levels in treated CML cells were analyzed by quantitative real-time PCR and Western blotting, and in vitro cell proliferation was assayed with the cell counting kit-8 method. The morphology and percentage of apoptosis were revealed by Hoechst 33258 staining and flow cytometry (FCM). The results demonstrated that both siRNAs had the best silencing results after nucleofection in all four cell lines and primary cells. A reduction in PPP2R5C mRNA and protein levels was observed in the treated cells. The proliferation rate of the PPP2R5C-siRNA-treated CML cell lines was significantly decreased at 72 h, and apoptosis was significantly increased. Significantly higher proliferation inhibition and apoptosis induction were found in K562R cells treated with PPP2R5C-siRNA799 than K562 cells. In conclusion, the suppression of PPP2R5C by RNA interference could inhibit proliferation and effectively induce apoptosis in CML cells that were either imatinib sensitive or resistant. Down-regulating PPP2R5C gene expression might be considered as a new therapeutic target strategy for CML, particularly for imatinib-resistant CML.

Dataset Information

Genetic and pharmacologic inhibition of ?-catenin targets imatinib-resistant leukemia stem cells in CML.

Publications

Genetic and pharmacologic inhibition of β-catenin targets imatinib-resistant leukemia stem cells in CML.

Similar Datasets

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