| Autor: |
Harb JG; 1] Human Cancer Genetics Program, Department Molecular Virology Immunology and Medical Genetics, Columbus, OH, USA [2] Blood Center of Wisconsin, Blood Research Institute, Milwaukee, WI, USA., Neviani P, Chyla BJ, Ellis JJ, Ferenchak GJ, Oaks JJ, Walker CJ, Hokland P, Roy DC, Caligiuri MA, Marcucci G, Huettner CS, Perrotti D |
| Jazyk: |
angličtina |
| Zdroj: |
Leukemia [Leukemia] 2013 Oct; Vol. 27 (10), pp. 1996-2005. Date of Electronic Publication: 2013 May 14. |
| DOI: |
10.1038/leu.2013.151 |
| Abstrakt: |
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: |
MEDLINE |
| Externí odkaz: |
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