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Specific, targetable interactions with the microenvironment influence imatinib-resistant chronic myeloid leukemia.

ABSTRACT: Therapy resistance in leukemia may be due to cancer cell-intrinsic and/or -extrinsic mechanisms. Mutations within BCR-ABL1, the oncogene giving rise to chronic myeloid leukemia (CML), lead to resistance to tyrosine kinase inhibitors (TKI), and some are associated with clinically more aggressive disease and worse outcome. Using the retroviral transduction/transplantation model of CML and human cell lines we faithfully recapitulate accelerated disease course in TKI resistance. We show in various models, that murine and human imatinib-resistant leukemia cells positive for the oncogene BCR-ABL1T315I differ from BCR-ABL1 native (BCR-ABL1) cells with regards to niche location and specific niche interactions. We implicate a pathway via integrin ?3, integrin-linked kinase (ILK) and its role in deposition of the extracellular matrix (ECM) protein fibronectin as causative of these differences. We demonstrate a trend towards a reduced BCR-ABL1T315I+ tumor burden and significantly prolonged survival of mice with BCR-ABL1T315I+ CML treated with fibronectin or an ILK inhibitor in xenogeneic and syngeneic murine transplantation models, respectively. These data suggest that interactions with ECM proteins via the integrin ?3/ILK-mediated signaling pathway in BCR-ABL1T315I+ cells differentially and specifically influence leukemia progression. Niche targeting via modulation of the ECM may be a feasible therapeutic approach to consider in this setting.

SUBMITTER: Kumar R

PROVIDER: S-EPMC7387317 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Specific, targetable interactions with the microenvironment influence imatinib-resistant chronic myeloid leukemia.

Kumar Rahul R Pereira Raquel S RS Zanetti Costanza C Minciacchi Valentina R VR Merten Maximilian M Meister Melanie M Niemann Julian J Dietz Marina S MS Rüssel Nina N Schnütgen Frank F Tamai Minori M Akahane Koshi K Inukai Takeshi T Oellerich Thomas T Kvasnicka Hans Michael HM Pfeifer Heike H Nicolini Franck E FE Heilemann Mike M Van Etten Richard A RA Krause Daniela S DS

Leukemia 20200521 8

Therapy resistance in leukemia may be due to cancer cell-intrinsic and/or -extrinsic mechanisms. Mutations within BCR-ABL1, the oncogene giving rise to chronic myeloid leukemia (CML), lead to resistance to tyrosine kinase inhibitors (TKI), and some are associated with clinically more aggressive disease and worse outcome. Using the retroviral transduction/transplantation model of CML and human cell lines we faithfully recapitulate accelerated disease course in TKI resistance. We show in various m ...[more]

PMID: 32439895

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Project description:Imatinib has been found to substantially improve outcomes in patients with chronic myeloid leukemia (CML) compared with previously available therapies. However, its use is complicated by development of resistance or drug intolerance, prompting dose escalation or a trial of dasatinib or nilotinib, the second-generation tyrosine kinase inhibitors (TKIs).This article reviews the mechanisms of TKI resistance; discusses the tolerability and efficacy of high-dose imatinib, dasatinib, and nilotinib; and provides background for the rational use of second-line treatment options.MEDLINE (1966-December 2009) and EMBASE (1993-December 2009) were searched for pertinent English-language publications using search terms that included, but were not limited to, chronic myeloid leukemia, imatinib, dasatinib, nilotinib, and clinical trial. Abstracts from American Society of Hematology annual meetings (2005-2009) were also reviewed. There were no prespecified inclusion or exclusion criteria.Major and complete cytogenetic responses (MCyR and CCyR, respectively) to second-line treatment with high-dose (600-800 mg/d PO) imatinib were restricted to CML patients who had achieved a CyR to standard-dose imatinib: >90% of patients without a previous CyR failed to respond. The expected durability of the response to this approach remains unclear. Grade 3/4 thrombocytopenia, neutropenia, and anemia occurred in 14%, 39%, and 8%, respectively, of patients receiving high-dose imatinib. In patients who failed first-line treatment with imatinib, dasatinib (70 mg BID PO) was associated with higher rates of CCyR at 2 years compared with imatinib (44% vs 18%, respectively; P = 0.003), as well as higher estimated rates of progression-free survival at 2 years (86% vs 65%; P = 0.001). Dasatinib use was complicated by grade 3/4 thrombocytopenia and neutropenia in 57% and 63% of patients, respectively, and pleural effusion in 5%. Nilotinib treatment was effective in patients who were resistant to or unable to tolerate imatinib, with 46% and 58% achieving a CCyR and MCyR, respectively, at 2 years. Nilotinib use was complicated by grade 3/4 thrombocytopenia and neutropenia in 28% and 40% of patients, respectively, and QTc-interval prolongation in 1% to 10% of patients. Neither agent was clinically effective in patients with the common T315I mutation.Dasatinib and nilotinib were effective and generally well tolerated as second-line treatments for CML patients with a suboptimal response to standard doses of imatinib or imatinib intolerance.

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

Specific, targetable interactions with the microenvironment influence imatinib-resistant chronic myeloid leukemia.

Publications

Specific, targetable interactions with the microenvironment influence imatinib-resistant chronic myeloid leukemia.

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