Autophagic degradation of the BCR-ABL oncoprotein and generation of antileukemic responses by arsenic trioxide
Autophagic degradation of the BCR-ABL oncoprotein and generation of antileukemic responses by arsenic trioxide
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DOI：
10.1182/blood-2012-01-402578
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发表时间：
2012-10-25
期刊：
影响因子：
20.3
通讯作者：
Platanias, Leonidas C.
中科院分区：
文献类型：
--
作者：
Goussetis, Dennis J.;Gounaris, Elias;Platanias, Leonidas C.
我们提供的证据表明，三氧化二砷（As 2 O3）通过一种新的机制，涉及p62/SQSTM 1介导的定位的癌蛋白的自体溶酶体和随后的降解介导的蛋白酶组织蛋白酶B的BCR-ABL癌蛋白的目标。我们的研究表明，自噬或组织蛋白酶B活性的抑制剂和/或p62/SQSTM 1、Atg 7或组织蛋白酶B的分子靶向可部分逆转AS（2）O（3）对表达BCR-ABL的白血病祖细胞（包括慢性髓细胞性白血病（CML）患者的原始白血病前体细胞）的抑制作用。总之，这些研究结果表明，自噬降解BCR-ABL的诱导As 2 O3的抗白血病作用是至关重要的，并提高了未来的治疗方法的潜力，通过调节元件的自噬机制，以促进BCR-ABL降解的目标BCR-ABL表达细胞。（血。2012;120（17）：3555-3562）
We provide evidence that arsenic trioxide (As2O3) targets the BCR-ABL oncoprotein via a novel mechanism involving p62/SQSTM1-mediated localization of the oncoprotein to the autolysosomes and subsequent degradation mediated by the protease cathepsin B. Our studies demonstrate that inhibitors of autophagy or cathepsin B activity and/or molecular targeting of p62/SQSTM1, Atg7, or cathepsin B result in partial reversal of the suppressive effects of AS(2)O(3) on BCR-ABL expressing leukemic progenitors, including primitive leukemic precursors from chronic myelogenous leukemia (CML) patients. Altogether, these findings indicate that autophagic degradation of BCR-ABL is critical for the induction of the antileukemic effects of As2O3 and raise the potential for future therapeutic approaches to target BCR-ABL expressing cells by modulating elements of the autophagic machinery to promote BCR-ABL degradation. (Blood. 2012;120(17):3555-3562)