BCL-2 family proteins as 5-Azacytidine-sensitizing targets and determinants of response in myeloid malignancies.
BCL-2 family proteins as 5-Azacytidine-sensitizing targets and determinants of response in myeloid malignancies.
复制标题
作者：
协同分子脆弱性增强低甲基化药物在髓系恶性肿瘤中仍然难以捉摸。rna干扰药物修饰剂筛选发现抗凋亡BCL-2家族成员是有效的5-氮杂胞苷增敏靶点。在进一步分析BCL-XL、BCL-2和MCL-1对5-氮杂胞苷活性的贡献时，体外实验显示，BCL-XL和MCL-1（而非BCL-2）的siRNA沉默与5-氮杂胞苷表现出可变的协同作用。与选择性BCL-2抑制剂ABT-199相比，BCL-XL、BCL-2和BCL-w抑制剂ABT-737对大多数细胞系具有更强的致敏性，后者在较高剂量下主要与5-氮杂胞苷协同作用。在体外，ABT-737增强了5-氮杂胞苷在原发性AML、MDS和MPN标本中的活性。577例AML患者样本中BCL-XL、BCL-2和MCL-1的蛋白水平显示出AML FAB亚型之间的重叠表达和亚型内的异质性表达，进一步支持了双/多重BCL-2家族成员靶向的概念，与RNAi和药理学结果一致。因此，MCL-1和BCL-XL的沉默增加了ABT-199的活性。通过对患者样本进行BH3谱分析对BCL-2家族蛋白进行功能分析，可以显著区分5-氮杂胞苷类药物的临床反应与耐药。基于这些结果，我们提出了navitoclax（临床级ABT-737）联合5-氮杂胞苷治疗髓系恶性肿瘤的临床试验，并前瞻性验证BH3谱分析预测5-氮杂胞苷反应的有效性。
Synergistic molecular vulnerabilities enhancing hypomethylating agents in myeloid malignancies have remained elusive. RNA-interference drug modifier screens identified antiapoptotic BCL-2 family members as potent 5-Azacytidine-sensitizing targets. In further dissecting BCL-XL, BCL-2 and MCL-1 contribution to 5-Azacytidine activity, siRNA silencing of BCL-XL and MCL-1, but not BCL-2, exhibited variable synergy with 5-Azacytidine in vitro. The BCL-XL, BCL-2 and BCL-w inhibitor ABT-737 sensitized most cell lines more potently compared with the selective BCL-2 inhibitor ABT-199, which synergized with 5-Azacytidine mostly at higher doses. Ex vivo, ABT-737 enhanced 5-Azacytidine activity across primary AML, MDS and MPN specimens. Protein levels of BCL-XL, BCL-2 and MCL-1 in 577 AML patient samples showed overlapping expression across AML FAB subtypes and heterogeneous expression within subtypes, further supporting a concept of dual/multiple BCL-2 family member targeting consistent with RNAi and pharmacologic results. Consequently, silencing of MCL-1 and BCL-XL increased the activity of ABT-199. Functional interrogation of BCL-2 family proteins by BH3 profiling performed on patient samples significantly discriminated clinical response versus resistance to 5-Azacytidine-based therapies. On the basis of these results, we propose a clinical trial of navitoclax (clinical-grade ABT-737) combined with 5-Azacytidine in myeloid malignancies, as well as to prospectively validate BH3 profiling in predicting 5-Azacytidine response.
登录
查看更多内容
影响因子：
45.3
作者：
Luebbert, Michael;Suciu, Stefan;Wijermans, Pierre W.
通讯作者：
Wijermans, Pierre W.
影响因子：
50.3
作者：
Certo, Michael;Moore, Victoria Del Gaizo;Letai, Anthony
通讯作者：
Letai, Anthony
影响因子：
45.3
作者：
Fenaux, Pierre;Mufti, Ghulam J.;Silverman, Lewis R.
通讯作者：
Silverman, Lewis R.
影响因子：
5.7
作者：
Kiziltepe, Tanyel;Hideshima, Teru;Anderson, Kenneth C.
通讯作者：
Anderson, Kenneth C.
影响因子：
2.7
作者：
Cherington, Chad;Slack, James L.;Mesa, Ruben A.
通讯作者：
Mesa, Ruben A.