Venetoclax responses of pediatric ALL xenografts reveal sensitivity of MLL-rearranged leukemia
Venetoclax responses of pediatric ALL xenografts reveal sensitivity of MLL-rearranged leukemia
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DOI：
10.1182/blood-2016-03-707414
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发表时间：
2016-09-08
期刊：
影响因子：
20.3
通讯作者：
Lock, Richard B.
中科院分区：
文献类型：
--
作者：
Khaw, Seong Lin;Suryani, Santi;Lock, Richard B.
BCL-2选择性BH3模拟维奈托克在预后不良的慢性淋巴细胞白血病（CLL）患者中的临床成功突出了在以前无法治疗的淋巴恶性肿瘤中靶向BCL-2调节的细胞凋亡途径的潜力。通过选择性抑制BCL-2，维奈托克避免了其选择性较低的前体navitoclax的剂量限制性、BCL-X-L介导的血小板减少症，同时增强了对CLL的疗效。我们以前曾报道过许多高危儿童急性淋巴细胞白血病（ALL）异种移植物对navitoclax的潜在敏感性。鉴于维奈托克的上级耐受性，我们在此研究了其在儿童ALL中的疗效。我们证明，与CLL对BCL-2单独的明显依赖相反，在大多数ALL异种移植物中有效的抗白血病活性需要同时抑制BCL-2和BCL-XL。我们确定BCL-XL表达是对维奈托克反应不良的关键预测因子，并证明BCL-2和BCL-XL的同时抑制导致大多数ALL异种移植物的协同杀伤。一个值得注意的例外是混合谱系白血病重排的婴儿ALL，其中维奈托克在很大程度上重现了navitoclax的活性，将该亚组患者确定为维奈托克治疗儿童ALL临床试验的潜在候选者。相反，我们的研究结果提供了一个明确的基础，在其他亚组中，navitoclax先于venetoclax进入试验。
The clinical success of the BCL-2-selective BH3-mimetic venetoclax in patients with poor prognosis chronic lymphocytic leukemia (CLL) highlights the potential of targeting the BCL-2-regulated apoptotic pathway in previously untreatable lymphoid malignancies. By selectively inhibiting BCL-2, venetoclax circumvents the dose-limiting, BCL-X-L-mediated thrombocytopenia of its less selective predecessor navitoclax, while enhancing efficacy in CLL. We have previously reported the potent sensitivity of many high-risk childhood acute lymphoblastic leukemia (ALL) xenografts to navitoclax. Given the superior tolerability of venetoclax, here we have investigated its efficacy in childhood ALL. We demonstrate that in contrast to the clear dependence of CLL on BCL-2 alone, effective antileukemic activity in the majority of ALL xenografts requires concurrent inhibition of both BCL-2 and BCL-XL. We identify BCL-XL expression as a key predictor of poor response to venetoclax and demonstrate that concurrent inhibition of both BCL-2 and BCL-XL results in synergistic killing in the majority of ALL xenografts. A notable exception is mixed lineage leukemia rearranged infant ALL, where venetoclax largely recapitulates the activity of navitoclax, identifying this subgroup of patients as potential candidates for clinical trials of venetoclax in childhood ALL. Conversely, our findings provide a clear basis for progressing navitoclax into trials ahead of venetoclax in other subgroups.