Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo 108-8639, Japan; Division of Molecular Pharmacology of Malignant Diseases, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-8654, Japan.
Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo 108-8639, Japan.
Cell Rep. 2024 Aug 27;43(8):114536. doi: 10.1016/j.celrep.2024.114536. Epub 2024 Aug 2.
Monocytic acute myeloid leukemia (AML) responds poorly to current treatments, including venetoclax-based therapy. We conducted in vivo and in vitro CRISPR-Cas9 library screenings using a mouse monocytic AML model and identified SETDB1 and its binding partners (ATF7IP and TRIM33) as crucial tumor promoters in vivo. The growth-inhibitory effect of Setdb1 depletion in vivo is dependent mainly on natural killer (NK) cell-mediated cytotoxicity. Mechanistically, SETDB1 depletion upregulates interferon-stimulated genes and NKG2D ligands through the demethylation of histone H3 Lys9 at the enhancer regions, thereby enhancing their immunogenicity to NK cells and intrinsic apoptosis. Importantly, these effects are not observed in non-monocytic leukemia cells. We also identified the expression of myeloid cell nuclear differentiation antigen (MNDA) and its murine counterpart Ifi203 as biomarkers to predict the sensitivity of AML to SETDB1 depletion. Our study highlights the critical and selective role of SETDB1 in AML with granulo-monocytic differentiation and underscores its potential as a therapeutic target for current unmet needs.
单核细胞性急性髓系白血病（AML）对当前的治疗方法反应不佳，包括基于 venetoclax 的治疗。我们使用小鼠单核细胞性 AML 模型进行了体内和体外 CRISPR-Cas9 文库筛选，并确定 SETDB1 及其结合蛋白（ATF7IP 和 TRIM33）是体内关键的肿瘤促进剂。Setdb1 在体内的抑制生长作用主要依赖于自然杀伤 (NK) 细胞介导的细胞毒性。从机制上讲，SETDB1 的耗竭通过增强子区域组蛋白 H3 Lys9 的去甲基化来上调干扰素刺激基因和 NKG2D 配体，从而增强它们对 NK 细胞和内在凋亡的免疫原性。重要的是，这些作用在非单核细胞性白血病细胞中观察不到。我们还确定了髓细胞核分化抗原 (MNDA) 的表达及其鼠类对应物 Ifi203 作为预测 AML 对 SETDB1 耗竭敏感性的生物标志物。我们的研究强调了 SETDB1 在具有粒单核细胞分化的 AML 中的关键和选择性作用，并强调了其作为当前未满足需求的治疗靶点的潜力。
