YM155 potently kills acute lymphoblastic leukemia cells through activation of the DNA damage pathway.
YM155 potently kills acute lymphoblastic leukemia cells through activation of the DNA damage pathway.
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DOI：
10.1186/s13045-015-0132-6
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发表时间：
2015-04-22
影响因子：
28.5
通讯作者：
Tyner JW
中科院分区：
文献类型：
--
作者：
Chang BH;Johnson K;LaTocha D;Rowley JS;Bryant J;Burke R;Smith RL;Loriaux M;Müschen M;Mullighan C;Druker BJ;Tyner JW
新的靶向治疗正在快速发展，用于治疗急性淋巴细胞白血病（ALL），以克服耐药性并降低毒性。Survivin是凋亡抑制基因家族和染色体乘客复合体的成员，在包括ALL在内的多种人类癌症中至关重要。存活素的一个公认的抑制因子是小分子YM 155。报告正在确定YM 155的其他作用机制。因此，我们试图研究YM 155在ALL治疗中的作用模式和作用。用YM 155询问原代ALL样品和ALL细胞系以鉴定药物敏感性。检测了携带BCR-ABL 1癌基因的Ph+ALL与YM 155和多激酶抑制剂达沙替尼的任何相互作用。使用标准生物化学测定以及RNA表达和磷酸化阵列测试代表性ALL细胞系以鉴定对YM 155的应答。ALL样本对YM 155表现出显著的敏感性，在Ph+ALL的情况下，观察到达沙替尼的叠加反应。ALL细胞在DNA复制过程中，S期对YM 155更敏感。YM 155激活DNA损伤途径，导致Chk 2和H2 AX的磷酸化。有趣的是，对主要患者样本的筛选在一些但不是所有标本中鉴定出独特且精致的YM 155敏感性。这些结果是第一次筛选了大量的原发性白血病患者样本，以确定对YM 155反应的个体差异。我们的研究进一步支持ALL中YM 155诱导DNA损伤导致S期阻滞。最后，只有ALL的亚群对YM 155具有极高的敏感性，可能是通过抑制生存素表达和激活DNA损伤途径，强调了其治疗开发的潜力。本文的在线版本（doi：10.1186/s13045-015-0132-6）包含补充材料，可供授权用户使用。
Novel-targeted therapies are in rapid development for the treatment of acute lymphoblastic leukemia (ALL) to overcome resistance and decrease toxicity. Survivin, a member of the inhibitor of apoptosis gene family and chromosome passenger complex, is critical in a variety of human cancers, including ALL. A well-established suppressor of survivin has been the small molecule, YM155. Reports are identifying other mechanisms of action for YM155. Therefore, we sought to investigate the mode of action and role of YM155 for therapeutic use in the context of ALL. Primary ALL samples and ALL cell lines were interrogated with YM155 to identify drug sensitivity. Ph+ALL harboring the BCR-ABL1 oncogene were tested for any interaction with YM155 and the multi-kinase inhibitor dasatinib. Representative ALL cell lines were tested to identify the response to YM155 using standard biochemical assays as well as RNA expression and phosphorylation arrays. ALL samples exhibited significant sensitivity to YM155, and an additive response was observed with dasatinib in the setting of Ph+ALL. ALL cells were more sensitive to YM155 during S phase during DNA replication. YM155 activates the DNA damage pathway leading to phosphorylation of Chk2 and H2AX. Interestingly, screening of primary patient samples identified unique and exquisite YM155 sensitivity in some but not all ALL specimens. These results are the first to have screened a large number of primary patient leukemic samples to identify individual variations of response to YM155. Our studies further support that YM155 in ALL induces DNA damage leading to S phase arrest. Finally, only subsets of ALL have exquisite sensitivity to YM155 presumably through both suppression of survivin expression and activation of the DNA damage pathway underscoring its potential for therapeutic development. The online version of this article (doi:10.1186/s13045-015-0132-6) contains supplementary material, which is available to authorized users.
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生存素选择性抑制剂 YM155 诱导 SK-NEP-1 Wilms 肿瘤细胞凋亡
影响因子：
3.8
作者：
Tao YF;Lu J;Du XJ;Sun LC;Zhao X;Peng L;Cao L;Xiao PF;Pang L;Wu D;Wang N;Feng X;Li YH;Ni J;Wang J;Pan J
通讯作者：
Pan J
EZN-3042 是一种新型生存素信使核糖核酸 (mRNA) 拮抗剂，与化疗联合治疗复发性急性淋巴细胞白血病 (ALL) 儿童的 I 期研究：儿童白血病和淋巴瘤 (TACL) 治疗进展报告财团。
DOI：
10.1097/mph.0b013e3182a8f58f
发表时间：
2014-08
期刊：
Journal of pediatric hematology/oncology
影响因子：
--
作者：
Raetz EA;Morrison D;Romanos-Sirakis E;Gaynon P;Sposto R;Bhojwani D;Bostrom BC;Brown P;Eckroth E;Cassar J;Malvar J;Buchbinder A;Carroll WL
通讯作者：
Carroll WL
影响因子：
3
作者：
Glaros, Trevor G.;Stockwin, Luke H.;Newton, Dianne L.
通讯作者：
Newton, Dianne L.
影响因子：
4.1
作者：
Li, FZ;Altieri, DC
通讯作者：
Altieri, DC
影响因子：
20.3
作者：
Park, Eugene;Gang, Eun Ji;Kim, Yong-Mi
通讯作者：
Kim, Yong-Mi