Bcl-xL anti-apoptotic network is dispensable for development and maintenance of CML but is required for disease progression where it represents a new therapeutic target
| Autor: | Christopher J. Walker, Denis-Claude Roy, B J Chyla, G. Marcucci, Joshua J. Oaks, Jason G. Harb, Paolo Neviani, Peter Hokland, Justin Ellis, Michael A. Caligiuri, Claudia S. Huettner, Gregory Ferenchak, Danilo Perrotti |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Male
Cancer Research Indoles CD34 Fusion Proteins bcr-abl bcl-X Protein Bcl-xL Antineoplastic Agents Apoptosis Mice Transgenic Article Mice Leukemia Myelogenous Chronic BCR-ABL Positive hemic and lymphatic diseases medicine Animals Humans Progenitor cell Sulfonamides Aniline Compounds biology Stem Cells Hematology medicine.disease Flow Cytometry Haematopoiesis Leukemia medicine.anatomical_structure Oncology Purines Immunology Cancer research biology.protein Disease Progression Female Bone marrow Stem cell Blast Crisis Chronic myelogenous leukemia |
| Zdroj: | Harb, J G, Neviani, P, Chyla, B J, Ellis, J J, Ferenchak, G J, Oaks, J J, Walker, C J, Hokland, P, Roy, D, Caligiuri, M A, Marcucci, G, Huettner, C S & Perrotti, D 2013, ' Bcl-xL anti-apoptotic network is dispensable for development and maintenance of CML but is required for disease progression where it represents a new therapeutic target ', Leukemia, vol. 27, no. 10, pp. 1996-2005 . https://doi.org/10.1038/leu.2013.151 |
| Popis: | The dismal outcome of blast crisis chronic myelogenous leukemia (CML-BC) patients underscores the need for a better understanding of the mechanisms responsible for the development of drug resistance. Altered expression of the anti-apoptoticBcl-xL has been correlated with BCR-ABL leukemogenesis; however, its involvement in the pathogenesis and evolution of CML has not been formally demonstrated yet. Thus, we generated an inducible mouse model in which simultaneous expression of p210-BCR-ABL1 and deletion of bcl-x occurs within hematopoietic stem and progenitor cells. Absence of Bcl-xL did not affect development of the chronic phase-like myeloproliferative disease, but none of the deficient mice progressed to an advanced phenotype, suggesting the importance of Bcl-xL in survival of progressing early progenitor cells. Indeed, pharmacological antagonism of Bcl-xL, with ABT-263, combined with PP242-induced activation of BAD markedly augmented apoptosis of CML-BC cell lines and primary CD34(+) progenitors but not those from healthy donors, regardless of drug resistance induced by bone marrow stromal cell-generated signals. Moreover, studies in which BAD or Bcl-xL expression was molecularly altered strongly support their involvement in ABT-263/PP242-induced apoptosis of CML-BC progenitors. Thus, suppression of the antiapoptotic potential of Bcl-xL together with BAD activation represents an effective pharmacological approach for patients undergoing blastic transformation. |
| Databáze: | OpenAIRE |
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