Leukemia Cell of Origin Influences Apoptotic Priming and Sensitivity to LSD1 Inhibition.
Leukemia Cell of Origin Influences Apoptotic Priming and Sensitivity to LSD1 Inhibition.
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DOI：
10.1158/2159-8290.cd-19-1469
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发表时间：
2020-10
期刊：
影响因子：
28.2
通讯作者：
Armstrong SA
中科院分区：
文献类型：
--
作者：
Cai SF;Chu SH;Goldberg AD;Parvin S;Koche RP;Glass JL;Stein EM;Tallman MS;Sen F;Famulare CA;Cusan M;Huang CH;Chen CW;Zou L;Cordner KB;DelGaudio NL;Durani V;Kini M;Rex M;Tian HS;Zuber J;Baslan T;Lowe SW;Rienhoff HY Jr;Letai A;Levine RL;Armstrong SA
致癌转化的起源细胞是治疗敏感性的决定因素，但起源细胞驱动的治疗反应差异的机制尚未阐明。与源自骨髓祖细胞的白血病相比，起源于造血干细胞（HSC）的白血病对化疗的敏感性较低，并且高度表达转录因子Evi 1。在这里，我们比较了造血干细胞或髓系祖细胞中的白血病，以揭示Evi 1在调节p53蛋白丰度和活性方面的新功能。HSC衍生的白血病表现出凋亡启动减少，p53转录输出减弱，以及对赖氨酸特异性去甲基化酶1抑制剂的抗性。Evi1low祖细胞衍生白血病中p53功能丧失诱导对LSD 1抑制的抗性，并且Evi1high白血病对维奈托克的LSD 1抑制敏感。我们的研究结果证明了p53野生型癌症中EVI1在降低p53功能方面的作用，并提供了一种策略来规避耐药EVI1高AML的耐药性。
The cell of origin of oncogenic transformation is a determinant of therapeutic sensitivity, but the mechanisms governing cell-of-origin-driven differences in therapeutic response have not been delineated. Leukemias initiating in hematopoietic stem cells (HSC) are less sensitive to chemotherapy and highly express the transcription factor Evi1 compared to leukemias derived from myeloid progenitors. Here, we compared leukemias initiated in either HSCs or myeloid progenitors to reveal a novel function for Evi1 in modulating p53 protein abundance and activity. HSC-derived leukemias exhibit decreased apoptotic priming, attenuated p53 transcriptional output, and resistance to lysine-specific demethylase 1 inhibitors in addition to classical genotoxic stresses. p53 loss-of-function in Evi1low progenitor-derived leukemias induces resistance to LSD1 inhibition, and Evi1high leukemias are sensitized to LSD1 inhibition by venetoclax. Our findings demonstrate a role for EVI1 in p53 wild-type cancers in reducing p53 function and provide a strategy to circumvent drug resistance in chemoresistant EVI1high AML.