Repression of TRIM13 by chromatin assembly factor CHAF1B is critical for AML development.
Repression of TRIM13 by chromatin assembly factor CHAF1B is critical for AML development.
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DOI：
10.1182/bloodadvances.2022009438
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发表时间：
2023-09-12
期刊：
影响因子：
7.5
通讯作者：
Volk, Andrew G.
中科院分区：
文献类型：
--
作者：
Dean, Sarai T.;Ishikawa, Chiharu;Zhu, Xiaoqin;Walulik, Sean;Nixon, Timothy;Jordan, Jessica K.;Henderson, Samantha;Wyder, Michael;Salomonis, Nathan;Wunderlich, Mark;Greis, Kenneth D.;Starczynowski, Daniel T.;Volk, Andrew G.
染色质组装机制通过直接调节E3泛素连接酶TRIM13的转录来保护白血病细胞的自我更新。TRIM13是核定位的，通过稳定细胞周期蛋白A1来驱动细胞周期进入，从而抑制自我更新。急性髓系白血病(AML)是一种侵袭性血癌，源于骨髓中未成熟白血病母细胞的快速扩张。表观遗传因素的突变是AML最大的遗传驱动因素类别。染色质组装因子CHAF1B是一种主要的表观遗传转录调节因子，与AML原始细胞的自我更新和未分化状态相关。在几乎所有AML样本中观察到的CHAF1B上调，通过抑制分化因子和肿瘤抑制因子的转录而促进白血病进展。然而，CHAF1B调控的特定因子及其在白血病发生中的作用尚不清楚。我们分析了来自小鼠MLL-AF9白血病细胞和骨髓抽提物的RNA测序数据，代表了儿童AML样本的不同集合，并确定E3泛素连接酶TRIM13是CHAF1B介导的与白血病发生相关的转录抑制的靶标。我们发现CHAF1B与TRIM13的启动子结合，导致其转录抑制。反过来，TRIM13通过其核定位和细胞周期促进蛋白CCNA1的催化泛素化，促进有害的进入细胞周期，从而抑制白血病细胞的自我更新。TRIM13的过表达最初导致AML细胞的增殖爆发，随后是衰竭，而总TRIM13的丢失或其催化结构域的缺失增加了AML细胞系和患者来源的异种移植的白血病发生。这些数据表明，CHAF1B促进白血病的发展，部分是通过抑制TRIM13的表达，这种关系对于白血病的进展是必要的。
The chromatin assembly machinery protects leukemic cell self-renewal by directly regulating transcription of the E3 ubiquitin ligase TRIM13. TRIM13 is nuclear localized and represses self-renewal by driving cell cycle entry through the stabilization of cyclin A1. Acute myeloid leukemia (AML) is an aggressive blood cancer that stems from the rapid expansion of immature leukemic blasts in the bone marrow. Mutations in epigenetic factors represent the largest category of genetic drivers of AML. The chromatin assembly factor CHAF1B is a master epigenetic regulator of transcription associated with self-renewal and the undifferentiated state of AML blasts. Upregulation of CHAF1B, as observed in almost all AML samples, promotes leukemic progression by repressing the transcription of differentiation factors and tumor suppressors. However, the specific factors regulated by CHAF1B and their contributions to leukemogenesis are unstudied. We analyzed RNA sequencing data from mouse MLL-AF9 leukemic cells and bone marrow aspirates, representing a diverse collection of pediatric AML samples and identified the E3 ubiquitin ligase TRIM13 as a target of CHAF1B-mediated transcriptional repression associated with leukemogenesis. We found that CHAF1B binds the promoter of TRIM13, resulting in its transcriptional repression. In turn, TRIM13 suppresses self-renewal of leukemic cells by promoting pernicious entry into the cell cycle through its nuclear localization and catalytic ubiquitination of cell cycle–promoting protein, CCNA1. Overexpression of TRIM13 initially prompted a proliferative burst in AML cells, which was followed by exhaustion, whereas loss of total TRIM13 or deletion of its catalytic domain enhanced leukemogenesis in AML cell lines and patient-derived xenografts. These data suggest that CHAF1B promotes leukemic development, in part, by repressing TRIM13 expression and that this relationship is necessary for leukemic progression.
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