The anti-apoptotic genes Bcl-XL and Bcl-2 are over-expressed and contribute to chemoresistance of non-proliferating leukaemic CD34+ cells
The anti-apoptotic genes Bcl-XL and Bcl-2 are over-expressed and contribute to chemoresistance of non-proliferating leukaemic CD34+ cells
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DOI：
10.1046/j.1365-2141.2002.03637.x
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发表时间：
2002-08-01
影响因子：
6.5
通讯作者：
Andreeff, M
中科院分区：
文献类型：
--
作者：
Konopleva, M;Zhao, SR;Andreeff, M
在急性髓系白血病 (AML) 中，细胞动力学静止被认为会导致耐药性。由于抗凋亡基因 Bcl-2 和 Bcl-X-L 与细胞周期调节有关，我们研究了这些基因在非增殖性 (Q) 和增殖性 (P) AML 以及正常 CD34(+) 祖细胞中的表达。使用逆转录聚合酶链反应，Bcl-X-L 和 Bcl-2 在 Q 与 P AML 细胞中过表达，而 Bcl-X-S 和 Bax 表达没有差异。此外，与正常CD34(+) Q细胞相比，Q AML中Bcl-X-L /X-S比率较高，但Bcl-2/Bax比率较高(P = 0.001)。发现白血病 Q 细胞的 Bcl-2 表达与其进入细胞周期的能力呈负相关。全反式视黄酸 (ATRA) 治疗可降低白血病 Q 细胞中 Bcl-2 和 Bcl-X-L 的表达，并增强其对胞嘧啶阿拉伯糖苷 (ara-C) 的化疗敏感性。这些发现表明抗凋亡蛋白Bcl-X-L和Bcl-2在静止的CD34(+) AML细胞中过度表达，并表明它们参与化疗耐药。观察到的 Bcl-2 与增殖之间的负相关表明 Bcl-2 在 AML 细胞周期调节中的作用。这些发现可用于开发选择性诱导静止白血病祖细胞凋亡的疗法。
In acute myeloid leukaemia (AML), cell kinetic quiescence has been postulated to contribute to drug resistance. As the anti-apoptotic genes Bcl-2 and Bcl-X-L have been implicated in cell cycle regulation, we investigated the expression of these genes in non-proliferating (Q) and proliferating (P) AML and normal CD34(+) progenitor cells. Using reverse transcription polymerase chain reaction, Bcl-X-L and Bcl-2 were overexpressed in Q versus P AML cells, whereas no difference in Bcl-X-S and Bax expression was found. Furthermore, the Bcl-X-L /X-S but not the Bcl-2/Bax ratio was higher in Q AML compared with normal CD34(+) Q cells (P = 0.001). An inverse correlation between Bcl-2 expression of leukaemic Q cells and their ability to enter the cell cycle was found. Treatment with all-trans retinoic acid (ATRA) reduced Bcl-2 and Bcl-X-L expression in the leukaemic Q cells, and enhanced their chemosensitivity to cytosine arabinoside (ara-C). These findings demonstrate overexpression of the anti-apoptotic proteins Bcl-X-L and Bcl-2 in quiescent CD34(+) AML cells and suggest their involvement in the chemoresistance. The observed inverse correlation between Bcl-2 and proliferation suggests a role for Bcl-2 in the cell cycle regulation of AML. These findings could be used in the development of therapies that selectively induce apoptosis in quiescent leukaemic progenitor cells.