H3K79me2/3 controls enhancer-promoter interactions and activation of the pan-cancer stem cell marker PROM1/CD133 in MLL-AF4 leukemia cells.
H3K79me2/3 controls enhancer-promoter interactions and activation of the pan-cancer stem cell marker PROM1/CD133 in MLL-AF4 leukemia cells.
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DOI：
10.1038/s41375-020-0808-y
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发表时间：
2021-01
期刊：
影响因子：
11.4
通讯作者：
Milne TA
中科院分区：
文献类型：
--
作者：
Godfrey L;Crump NT;O'Byrne S;Lau IJ;Rice S;Harman JR;Jackson T;Elliott N;Buck G;Connor C;Thorne R;Knapp DJHF;Heidenreich O;Vyas P;Menendez P;Inglott S;Ancliff P;Geng H;Roberts I;Roy A;Milne TA
MLL基因重排(MLLr)是婴儿和儿童侵袭性、不可治愈的急性淋巴细胞白血病(ALL)的常见原因，其中大部分起源于子宫。最常见的MLLr产生MLL-AF4融合蛋白。MLL-AF4通过激活关键靶基因促进白血病的发生，主要是通过招募DOT1L和增加组蛋白H3赖氨酸-79甲基化(H3K79me2/3)。一个关键的MLL-AF4靶基因是编码CD133(Prominin-1)的PROM1。CD133是一种五聚糖跨膜糖蛋白，在多个癌症干细胞上发现，它代表着一个潜在的泛癌靶点。在这里，我们证明了PROM1/CD133的异常表达对于白血病细胞的生长是必不可少的，这是通过与MLL-AF4的直接结合来介导的。激活由基因内的H3K79me2/3增强子元件(KEE)控制，导致PROM1和邻近基因TAPT1之间的增强子-启动子相互作用增加。这种双基因位点调节反映在白血病中表达的强烈相关性中。我们发现，在PROM1/CD133非表达细胞中，PROM1基因座被多梳抑制复合体2(PRC2)结合抑制，与TAPT1表达降低相关，部分原因是失去了与PROM1基因座的相互作用。总之，这些结果提供了第一个详细的PROM1/CD133调控分析，解释了CD133在MLLr ALL中的表达。
MLL gene rearrangements (MLLr) are a common cause of aggressive, incurable acute lymphoblastic leukemias (ALL) in infants and children, most of which originate in utero. The most common MLLr produces an MLL-AF4 fusion protein. MLL-AF4 promotes leukemogenesis by activating key target genes, mainly through recruitment of DOT1L and increased histone H3 lysine-79 methylation (H3K79me2/3). One key MLL-AF4 target gene is PROM1, which encodes CD133 (Prominin-1). CD133 is a pentaspan transmembrane glycoprotein that represents a potential pan-cancer target as it is found on multiple cancer stem cells. Here we demonstrate that aberrant PROM1/CD133 expression is essential for leukemic cell growth, mediated by direct binding of MLL-AF4. Activation is controlled by an intragenic H3K79me2/3 enhancer element (KEE) leading to increased enhancer–promoter interactions between PROM1 and the nearby gene TAPT1. This dual locus regulation is reflected in a strong correlation of expression in leukemia. We find that in PROM1/CD133 non-expressing cells, the PROM1 locus is repressed by polycomb repressive complex 2 (PRC2) binding, associated with reduced expression of TAPT1, partially due to loss of interactions with the PROM1 locus. Together, these results provide the first detailed analysis of PROM1/CD133 regulation that explains CD133 expression in MLLr ALL.
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婴儿MLL重新培养急性淋巴细胞白血病中体细胞突变的景观。
影响因子：
30.8
作者：
Andersson AK;Ma J;Wang J;Chen X;Gedman AL;Dang J;Nakitandwe J;Holmfeldt L;Parker M;Easton J;Huether R;Kriwacki R;Rusch M;Wu G;Li Y;Mulder H;Raimondi S;Pounds S;Kang G;Shi L;Becksfort J;Gupta P;Payne-Turner D;Vadodaria B;Boggs K;Yergeau D;Manne J;Song G;Edmonson M;Nagahawatte P;Wei L;Cheng C;Pei D;Sutton R;Venn NC;Chetcuti A;Rush A;Catchpoole D;Heldrup J;Fioretos T;Lu C;Ding L;Pui CH;Shurtleff S;Mullighan CG;Mardis ER;Wilson RK;Gruber TA;Zhang J;Downing JR;St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project
通讯作者：
St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project
影响因子：
5.2
作者：
Ballabio E;Milne TA
通讯作者：
Milne TA
影响因子：
20.3
作者：
Harvey, Richard C.;Mullighan, Charles G.;Willman, Cheryl L.
通讯作者：
Willman, Cheryl L.
影响因子：
20.3
作者：
Khaw, Seong Lin;Suryani, Santi;Lock, Richard B.
通讯作者：
Lock, Richard B.
影响因子：
2.6
作者：
Hay SB;Ferchen K;Chetal K;Grimes HL;Salomonis N
通讯作者：
Salomonis N