Pharmacological Inhibition of PIM Kinases In Chronic Lymphocytic Leukemia Cases with Unfavorable Prognosis Markers
| Autor: | Julio Delgado, Elena Domenech, James R. Bischoff, Jose Francisco Tomas, Margarita Sánchez-Beato, Beatriz Herreros, Joaquin Martinez-Lopez, Carmen Blanco, María Eugenia Rodríguez, Raquel Villuendas, Antonia Rodriguez, Miguel A. Piris, Raul Cordoba, Cristina Gómez-Abad, José A. García-Marco, Juan F. García |
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| Rok vydání: | 2010 |
| Předmět: | |
| Zdroj: | Web of Science |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood.v116.21.2468.2468 |
| Popis: | Abstract 2468 Introduction: Pim kinases are a family of oncogenic kinases that has been demonstrated to play a role in B-cell development and lymphomagenesis, and proposed as Chronic Lymphocytic Leukemia (CLL) therapeutic target. An increased expression of PIM1 and PIM2 has been found in subsets of CLL and other B-cell lymphoma types. In order to further explore PIM inhibition as a rational therapeutic target, we decided to test a new pan-Pim kinase inhibitor, ETP-39010, developed by the Experimental Therapeutics Programme at the CNIO. Materials and methods: Blood samples from 16 CLL patients were collected by the Tumor Bank Unit at the CNIO. Samples were processed in order to separate B cells (RosetteSep® Human B cell enrichment Cocktail, Stem cell Technologies). Sensitivity to the compound was analyzed by EC50 calculations using the Cell Titer Glo® commercial kit from Promega. Gene expression data were normalized and preprocessed using GEPAS utility available at http://gepas.bioinfo.cipf.es/. Differentially expressed genes and pathways were obtained using T-Rex (GEPAS) or GSEA (http://www.broadinstitute.org/gsea/) bioinformatic tools respectively. Apoptosis was measured by Annexin V/ PI staining and cell cycle was studied by PI staining using flow cytometry. Results: A significant variability in ETP-39010 sensitivity was found in this series of B-CLL samples, with EC50 values ranging from 1,3 nM to 22,6 nM, consistently with the heterogeneous PIM expression levels observed in CLL cases. A higher sensitivity to the compound was identified in samples with markers of unfavorable outcome, such as ZAP70 positivity (p Conclusion: Inhibition of PIM kinases by ETP-39010 induces apoptosis in CLL samples. An increased sensitivity to PIM inhibition has been found in CLL cases with unfavourable prognostic markers, such as unmutated immunoglobulin heavy chain (IGHV) and increased expression of ZAP70 and LPL, pointing out PIM kinases as a potential therapeutic target for unmutated CLL. Disclosures: Garcia-Marco: ROCHE: Consultancy, Honoraria, Research Funding. |
| Databáze: | OpenAIRE |
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