Osimertinib Covalently Binds to CD34 and Eliminates Myeloid Leukemia Stem/Progenitor Cells.
Osimertinib Covalently Binds to CD34 and Eliminates Myeloid Leukemia Stem/Progenitor Cells.
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DOI：
10.1158/0008-5472.can-23-1632
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发表时间：
2024-02-01
期刊：
影响因子：
11.2
通讯作者：
中科院分区：
文献类型：
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作者：
奥西替尼结合CD34并选择性杀死CD34+白血病细胞，以诱导临床前模型和具有高比例CD34+原细胞的AML患者缓解，为髓系白血病患者提供治疗选择。奥西替尼是第三代共价EGFR抑制剂，用于治疗非小细胞肺癌。第一代EGFR抑制剂在临床前研究中被发现对急性髓性白血病（AML）细胞具有促分化作用，但临床试验结果大多为阴性。在这里，我们报告了奥西替尼选择性地诱导CD34+白血病干细胞/祖细胞凋亡，而不是CD34 -细胞在egfr阴性AML和慢性髓性白血病（CML）中凋亡。奥西替尼与CD34在199和177半胱氨酸位点的共价结合以及Src家族激酶（SFK）的抑制和下游STAT3的激活导致了奥西替尼诱导的细胞死亡。SFK和STAT3抑制可诱导奥西替尼对原代CD34+细胞的合成致死。与正常细胞相比，AML细胞中的CD34表达升高。基因组学、转录组学和蛋白质组学分析鉴定了CD34高表达AML患者的突变和基因表达特征，单因素和多因素分析表明CD34高表达对预后有不良影响。奥西替尼治疗在AML患者来源的异种移植模型中诱导了与CD34表达相关的反应，同时保留了正常的CD34+细胞。两名cd34高水平AML患者在同情用药基础上接受奥西替尼治疗，观察到临床反应。这些发现揭示了奥西替尼治疗cd34高的AML和CML的治疗潜力，并描述了奥西替尼诱导髓性白血病细胞死亡的不依赖egfr的机制。奥西替尼结合CD34并选择性杀死CD34+白血病细胞，以诱导临床前模型和具有高比例CD34+原细胞的AML患者缓解，为髓系白血病患者提供治疗选择。
Osimertinib binds CD34 and selectively kills CD34+ leukemia cells to induce remission in preclinical models and patients with AML with a high percentage of CD34+ blasts, providing therapeutic options for myeloid leukemia patients. Osimertinib is a third-generation covalent EGFR inhibitor that is used in treating non–small cell lung cancer. First-generation EGFR inhibitors were found to elicit pro-differentiation effect on acute myeloid leukemia (AML) cells in preclinical studies, but clinical trials yielded mostly negative results. Here, we report that osimertinib selectively induced apoptosis of CD34+ leukemia stem/progenitor cells but not CD34− cells in EGFR-negative AML and chronic myeloid leukemia (CML). Covalent binding of osimertinib to CD34 at cysteines 199 and 177 and suppression of Src family kinases (SFK) and downstream STAT3 activation contributed to osimertinib-induced cell death. SFK and STAT3 inhibition induced synthetic lethality with osimertinib in primary CD34+ cells. CD34 expression was elevated in AML cells compared with their normal counterparts. Genomic, transcriptomic, and proteomic profiling identified mutation and gene expression signatures of patients with AML with high CD34 expression, and univariate and multivariate analyses indicated the adverse prognostic significance of high expression of CD34. Osimertinib treatment induced responses in AML patient-derived xenograft models that correlated with CD34 expression while sparing normal CD34+ cells. Clinical responses were observed in two patients with CD34high AML who were treated with osimertinib on a compassionate-use basis. These findings reveal the therapeutic potential of osimertinib for treating CD34high AML and CML and describe an EGFR-independent mechanism of osimertinib-induced cell death in myeloid leukemia. Osimertinib binds CD34 and selectively kills CD34+ leukemia cells to induce remission in preclinical models and patients with AML with a high percentage of CD34+ blasts, providing therapeutic options for myeloid leukemia patients.
影响因子：
17.1
作者：
Saito Y;Mochizuki Y;Ogahara I;Watanabe T;Hogdal L;Takagi S;Sato K;Kaneko A;Kajita H;Uchida N;Fukami T;Shultz LD;Taniguchi S;Ohara O;Letai AG;Ishikawa F
通讯作者：
Ishikawa F