Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies
Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies
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DOI：
10.1016/j.ccell.2019.08.005
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发表时间：
2019-10-14
期刊：
影响因子：
50.3
通讯作者：
Wu, Catherine J.
中科院分区：
文献类型：
--
作者：
Guieze, Romain;Liu, Vivian M.;Wu, Catherine J.
FDA批准的B细胞淋巴瘤2（BCL-2）抑制剂venetoclax可有效靶向淋巴系统恶性肿瘤中的线粒体凋亡，但对该药物的耐药性正在出现。我们发现慢性淋巴细胞白血病的维奈托克耐药与复杂的克隆转移有关。为了确定耐药的决定因素，我们进行了平行的基因组规模的筛选BCL-2驱动的OCI-Ly 1淋巴瘤细胞系后，威尼托克暴露沿着与综合表达谱和功能特性的耐药和工程细胞系。我们确定了淋巴转录和细胞能量代谢的调节因子作为维奈托克耐药的驱动因素，此外还确定了BCL-2家族成员的已知参与，这在患者样本中得到了证实。我们的数据支持与代谢调节剂的组合治疗的实施，以解决维奈托克耐药性。
Mitochondrial apoptosis can be effectively targeted in lymphoid malignancies with the FDA-approved B cell lymphoma 2 (BCL-2) inhibitor venetoclax, but resistance to this agent is emerging. We show that venetoclax resistance in chronic lymphocytic leukemia is associated with complex clonal shifts. To identify determinants of resistance, we conducted parallel genome-scale screens of the BCL-2-driven OCI-Ly1 lymphoma cell line after venetoclax exposure along with integrated expression profiling and functional characterization of drug-resistant and engineered cell lines. We identified regulators of lymphoid transcription and cellular energy metabolism as drivers of venetoclax resistance in addition to the known involvement by BCL-2 family members, which were confirmed in patient samples. Our data support the implementation of combinatorial therapy with metabolic modulators to address venetoclax resistance.