Modulation of Navitoclax Sensitivity by Dihydroarteminisin-Mediated MCL-1 Repression

Poor prognosis BCR-ABL+ B-ALL leukemic cells are highly dependent on the expression of endogenous anti-apoptotic MCL-1. However, the survival of most normal blood cells (e.g. progenitors, lymphocytes, and granulocytes) and other normal cell types (e.g. cardiomyocytes and neurons) are also exquisitely dependent on Mcl-1 gene expression, suggesting that effective therapeutic inhibition of MCL-1 could be acutely toxic, especially when combined with standard chemotherapy. Therefore, as an alternative to MCL-1 inhibition, we have identified dihydroarteminisin (DHA), a water-soluble metabolite of the anti-malarial arteminisin, which induces the down-modulation of MCL-1 protein expression by triggering an endoplasmic reticulum stress response. The DHA induced repression of MCL-1 expression renders leukemic cells highly sensitive to synergistic cell death induced by BH3-mimetic agents such as navitoclax (ABT-263) in a mouse model of BCR-ABL+ B-ALL. Furthermore, DHA also synergizes with navitoclax in human Ph+ ALL cell lines, and primary patient derived xenografts of Ph+ ALL. These data demonstrate that combining DHA with BH3-mimetic agents can improve therapeutic response in poor prognosis leukemia. We used microarrays to compare the DHA treatement to controls in mice.

预后不良的BCR-ABL阳性B系急性淋巴细胞白血病（BCR-ABL+ B-ALL）细胞高度依赖内源性抗凋亡MCL-1的表达。然而，多数正常血细胞（如造血祖细胞、淋巴细胞与粒细胞）及其他正常细胞类型（如心肌细胞与神经元）的存活同样严格依赖Mcl-1基因的表达，这提示有效的MCL-1治疗性抑制可能引发急性毒性，尤其在与标准化疗联合使用时。因此，作为MCL-1抑制的替代策略，我们鉴定出双氢青蒿素（dihydroarteminisin, DHA）——一种抗疟药物青蒿素的水溶性代谢产物——其可通过触发内质网应激反应（endoplasmic reticulum stress response）下调MCL-1蛋白的表达。在BCR-ABL+ B-ALL小鼠模型中，DHA介导的MCL-1表达抑制可使白血病细胞对BH3模拟物（BH3-mimetic agents）如navitoclax（ABT-263）诱导的协同细胞死亡高度敏感。此外，DHA在人费城染色体阳性急性淋巴细胞白血病（Ph+ ALL）细胞系以及原发性Ph+ ALL患者来源异种移植模型中，同样可与navitoclax产生协同作用。上述数据表明，将DHA与BH3模拟物联合使用，可改善预后不良白血病的治疗响应。我们采用微阵列（microarrays）技术，对比了小鼠体内DHA处理组与对照组的基因表达差异。