Sustained leukaemic phenotype after inactivation of BCR-ABLp190 in mice
Sustained leukaemic phenotype after inactivation of BCR-ABLp190 in mice
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DOI：
10.1038/sj.onc.1209968
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发表时间：
2007-03-01
期刊：
影响因子：
8
通讯作者：
Sanchez-Garcia, I.
中科院分区：
文献类型：
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作者：
Perez-Caro, M.;Gutierrez-Cianca, N.;Sanchez-Garcia, I.
癌症基因或产物的药物失活正被用作肿瘤学治疗的一种策略。为了研究bcr-ABLp190停止在白血病发展中的潜在作用，我们产生了携带四环素可抑制的bcr-ABLp190转基因的小鼠。这些小鼠出生时形态正常，并患上了白血病。疾病的特征是B细胞母细胞共表达髓系标志，这让人想起人类的同类。BCR-ABLp190的激活可引发幼年和成年小鼠的白血病。Bcr-ABLp190的瞬时表达足以导致白血病的发生。抑制BCR-ABLp190转基因在白血病CombitTA-p190小鼠中不能挽救恶性表型，表明BCR-ABLp190不是维持小鼠疾病所必需的。在白血病CombitTA-p190小鼠中，用STI571(Gleevec；Novartis，East Hanover，NJ，USA)灭活BCR-ABLp190也获得了类似的结果。然而，在白血病CombitTA-p190小鼠中逐渐抑制BCR-ABLp190发现了逆转白血病细胞中B细胞分化的特定阻断所需的最低水平的BCR-ABLp190表达。总体而言，研究结果表明，BCR-ABLp190似乎在维持肿瘤的细胞中引起表观遗传和/或遗传变化，使它们对BCR-ABLp190失活不敏感。
Pharmacological inactivation of cancer genes or products is being used as a strategy for therapy in oncology. To investigate the potential role of BCR-ABLp190 cessation in leukaemia development, we generated mice carrying a tetracycline-repressible BCR-ABLp190 transgene. These mice were morphologically normal at birth, and developed leukaemias. Disease was characterized by the presence of B-cell blasts co-expressingmyeloid markers, reminiscent of the human counterpart. BCR-ABLp190 activation can initiate leukaemia in both young and adult mice. Transitory expression of BCR-ABLp190 is enough to develop leukaemia. Suppression of the BCR-ABLp190 transgene in leukaemic CombitTA-p190 mice did not rescue the malignant phenotype, indicating that BCR-ABLp190 is not required to maintain the disease in mice. Similar results were obtained by inactivation of BCR-ABLp190 with STI571 (Gleevec; Novartis, East Hanover, NJ, USA) in leukaemic CombitTA-p190 mice. However, gradual suppression of BCR-ABLp190 in leukaemic CombitTA-p190 mice identified a minimum level of BCR-ABLp190 expression necessary to revert the specific block in B-cell differentiation in the leukaemic cells. Overall, the findings indicate that BCR-ABLp190 appears to cause epigenetic and/or genetic changes in tumour-maintaining cells that render them insensitive to BCR-ABLp190 inactivation.