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.
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.
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原始细胞危象慢性粒细胞白血病(CML-BC)患者的悲惨结局强调了更好地了解导致耐药性产生的机制的必要性。抗凋亡基因Bclxl的表达改变与bcr-abl白血病的发生有关，但其在CML的发病和演变中的作用尚未得到正式证实。因此，我们建立了一种可诱导的小鼠模型，在该模型中，p210-bcr-abl1的表达和bclx的缺失同时发生在造血干和祖细胞中。Bclxl的缺失并不影响慢性时相样骨髓增殖性疾病的发展，但没有一只缺陷的小鼠进展到晚期表型，这表明Bclxl在进展中的早期祖细胞的生存中具有重要意义。事实上，Bclxl与ABT-263的药理拮抗作用与pp242诱导的BAD激活相结合，显著增加了CML-BC细胞株和原代CD34+祖细胞的凋亡，但不包括来自健康供者的细胞，无论骨髓基质细胞产生的信号诱导耐药。此外，分子水平改变Bad或Bclxl表达的研究强烈支持它们参与ABT-263/pp242诱导的CML-BC祖细胞的凋亡。因此，抑制Bc l-xl的抗凋亡潜能，并结合不良的激活，是一种有效的药理学方法，可用于急变期患者。
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-apoptotic Bcl-xL has been correlated with BCR-ABL leukemogenesis; however, its involvement in the pathogenesis and evolution of CML has not been formally been 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, pharmacologic 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 pharmacologic approach for patients undergoing blastic transformation.
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