Leukemia cell of origin influences apoptotic priming and sensitivity to LSD1 inhibition

Previous studies have established that the cell of origin of oncogenic transformation is a determinant of therapeutic sensitivity. However, 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 cytotoxic chemotherapy and express high levels of the transcription factor Evi1 compared to leukemias derived from myeloid progenitors. Here, we compared drug sensitivity and expression profiles of murine and human leukemias initiated in either HSCs or myeloid progenitors to reveal a novel function for Evi1 in modulating p53 protein stability 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. By contrast, Evi1high leukemias are sensitized to LSD1 inhibition by the BH3 mimetic venetoclax, resulting in enhanced apoptosis and greater reductions in disease burden. Our findings demonstrate a cell-of-origin determined novel role for EVI1 in p53 wild-type cancers in reducing p53 function and provide a strategy to circumvent drug resistance in high-risk, chemoresistant EVI1high AML. RNA-seq of bone marrow-derived stem and progenitor cells transformed by MLL-AF9

既往研究已证实，致癌转化的起源细胞是决定治疗敏感性的核心因素。然而，调控起源细胞介导的治疗反应差异的分子机制尚未被阐明。与髓系祖细胞来源的白血病相比，起源于造血干细胞（hematopoietic stem cells, HSC）的白血病对细胞毒性化疗的敏感性更低，且转录因子Evi1的表达水平显著更高。本研究通过比较造血干细胞或髓系祖细胞来源的小鼠与人类白血病的药物敏感性及表达谱，揭示了Evi1在调控p53蛋白稳定性与活性中的全新功能。造血干细胞来源的白血病不仅对经典基因毒性应激具有抗性，还表现出凋亡致敏性降低、p53转录活性减弱以及对赖氨酸特异性去甲基化酶1（lysine-specific demethylase 1, LSD1）抑制剂耐药的特征。在Evi1低表达的祖细胞来源白血病中，p53功能缺失会诱导其对LSD1抑制剂产生耐药性。与之相反，经BH3模拟物维奈克拉（venetoclax）处理后，Evi1高表达白血病可被增敏至LSD1抑制剂，进而增强细胞凋亡并更显著地降低疾病负荷。本研究结果证实，在p53野生型癌症中，EVI1可通过起源细胞依赖性机制下调p53功能，这一全新功能为高危、化疗耐药的EVI1高表达急性髓系白血病（acute myeloid leukemia, AML）提供了规避耐药性的治疗策略。本研究针对经MLL-AF9转化的骨髓来源干细胞及祖细胞开展了RNA测序（RNA-seq）。