SETDB2 Links E2A-PBX1 to Cell-Cycle Dysregulation in Acute Leukemia through CDKN2C Repression.
SETDB2 Links E2A-PBX1 to Cell-Cycle Dysregulation in Acute Leukemia through CDKN2C Repression.
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DOI：
10.1016/j.celrep.2018.03.124
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发表时间：
2018-04-24
期刊：
影响因子：
8.8
通讯作者：
Cleary ML
中科院分区：
文献类型：
--
作者：
Lin CH;Wong SH;Kurzer JH;Schneidawind C;Wei MC;Duque-Afonso J;Jeong J;Feng X;Cleary ML
急性淋巴细胞白血病（ALL）与显著的发病率和死亡率相关，需要进一步改进诊断和治疗。针对染色质调节因子的靶向治疗正在临床前研究和早期临床试验中成为有前途的方法。在这里，我们证明了蛋白质赖氨酸甲基转移酶SETDB 2在白血病发病机制中的致癌作用。它在前BCR + ALL中过表达，并且是它们在体外和体内维持所必需的。SETDB 2表达在ALL亚群中作为嵌合转录因子E2 A-PBX 1的直接靶基因，并通过组蛋白H3 K9三甲基化抑制细胞周期抑制剂CDKN 2C的表达，从而建立了一种从属于E2 A-PBX 1的致癌途径，使ALL中的主要肿瘤抑制因子沉默。相比之下，SETDB 2对正常造血干细胞和祖细胞增殖相对较弱。SETDB 2敲低增强了对激酶和染色质抑制剂的敏感性，为ALL中靶向SETDB 2的治疗提供了机制原理。简而言之：Lin等报道，蛋白质赖氨酸甲基转移酶SETDB 2是嵌合转录因子E2 A-PBX 1的直接靶点，并且是B细胞前体白血病发病所必需的。SETDB 2抑制细胞周期抑制剂CDKN 2C的表达，建立了一种致癌途径，使急性白血病中的主要肿瘤抑制因子沉默。
Acute lymphoblastic leukemia (ALL) is associated with significant morbidity and mortality, necessitating further improvements in diagnosis and therapy. Targeted therapies directed against chromatin regulators are emerging as promising approaches in preclinical studies and early clinical trials. Here, we demonstrate an oncogenic role for the protein lysine methyltransferase SETDB2 in leukemia pathogenesis. It is overexpressed in pre-BCR+ ALL and required for their maintenance in vitro and in vivo. SETDB2 expression is maintained as a direct target gene of the chimeric transcription factor E2A-PBX1 in a subset of ALL and suppresses expression of the cell-cycle inhibitor CDKN2C through histone H3K9 tri-methylation, thus establishing an oncogenic pathway subordinate to E2A-PBX1 that silences a major tumor suppressor in ALL. In contrast, SETDB2 was relatively dispensable for normal hematopoietic stem and progenitor cell proliferation. SETDB2 knockdown enhances sensitivity to kinase and chromatin inhibitors, providing a mechanistic rationale for targeting SETDB2 therapeutically in ALL. In Brief: Lin et al. report that the protein lysine methyltransferase SETDB2 is a direct target of chimeric transcription factor E2A-PBX1 and required for pathogenesis in B cell precursor leukemia. SETDB2 suppresses expression of the cell-cycle inhibitor CDKN2C, establishing an oncogenic pathway that silences a major tumor suppressor in acute leukemia.
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影响因子：
12.8
作者：
Da Costa, D.;Agathanggelou, A.;Perry, T.;Weston, V.;Petermann, E.;Zlatanou, A.;Oldreive, C.;Wei, W.;Stewart, G.;Longman, J.;Smith, E.;Kearns, P.;Knapp, S.;Stankovic, T.
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Stankovic, T.
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影响因子：
3.8
作者：
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通讯作者：
Eklund, Elizabeth A.
影响因子：
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作者：
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影响因子：
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作者：
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Tanaka S
影响因子：
50.3
作者：
Geng H;Hurtz C;Lenz KB;Chen Z;Baumjohann D;Thompson S;Goloviznina NA;Chen WY;Huan J;LaTocha D;Ballabio E;Xiao G;Lee JW;Deucher A;Qi Z;Park E;Huang C;Nahar R;Kweon SM;Shojaee S;Chan LN;Yu J;Kornblau SM;Bijl JJ;Ye BH;Ansel KM;Paietta E;Melnick A;Hunger SP;Kurre P;Tyner JW;Loh ML;Roeder RG;Druker BJ;Burger JA;Milne TA;Chang BH;Müschen M
通讯作者：
Müschen M