Enhancers of Polycomb EPC1 and EPC2 sustain the oncogenic potential of MLL leukemia stem cells.
Enhancers of Polycomb EPC1 and EPC2 sustain the oncogenic potential of MLL leukemia stem cells.
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通过对染色质调控基因的靶向敲除（KD）筛选，我们鉴定出EP 400复合物组分EPC 1和EPC 2为急性髓性白血病（AML）中的关键致癌辅因子。EPC 1和EPC 2是多种分子亚型的人AML细胞的克隆形成潜力所必需的。以ML突变的AML为例，Epc 1或Epc 2 KD诱导小鼠MLL-AF 9 AML细胞凋亡，并消除白血病干细胞潜能。相比之下，正常造血干细胞和祖细胞（HSPC）幸免。在人原代AML细胞与正常CD 34 + HSPC中观察到相似的选择性。与这些不同的功能结果一致，Epc 1或Epc 2 KD在鼠MLL-AF 9粒细胞-巨噬细胞祖细胞样（GMP）细胞中诱导了与正常GMP不同的转录结果，在白血病细胞而不是正常细胞中具有MYC活性增加的特征。这是由MYC蛋白的积累引起的，并且在其他EP 400复合体基因的KD之后也观察到。MYC：MAX二聚化或伴随的MYC KD的药理学抑制减少了EPC 1 KD后的细胞凋亡，将MYC的积累与细胞死亡联系起来。因此，EPC 1和EPC 2是复合物的组成部分，直接或间接地用于防止MYC积聚和AML细胞凋亡，从而维持致癌潜力。
Through a targeted knockdown (KD) screen of chromatin regulatory genes we identified the EP400 complex components EPC1 and EPC2 as critical oncogenic co-factors in acute myeloid leukemia (AML). EPC1 and EPC2 were required for the clonogenic potential of human AML cells of multiple molecular subtypes. Focusing on MLL-mutated AML as an exemplar, Epc1 or Epc2 KD induced apoptosis of murine MLL-AF9 AML cells and abolished leukemia stem cell potential. By contrast, normal hematopoietic stem and progenitor cells (HSPC) were spared. Similar selectivity was observed for human primary AML cells versus normal CD34+ HSPC. In keeping with these distinct functional consequences, Epc1 or Epc2 KD induced divergent transcriptional consequences in murine MLL-AF9 granulocyte-macrophage progenitor-like (GMP) cells versus normal GMP, with a signature of increased MYC activity in leukemic but not normal cells. This was caused by accumulation of MYC protein and was also observed following KD of other EP400 complex genes. Pharmacological inhibition of MYC:MAX dimerization, or concomitant MYC KD, reduced apoptosis following EPC1 KD, linking the accumulation of MYC to cell death. Therefore EPC1 and EPC2 are components of a complex which directly or indirectly serves to prevent MYC accumulation and AML cell apoptosis, thus sustaining oncogenic potential.
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影响因子：
64.5
作者：
Kim J;Woo AJ;Chu J;Snow JW;Fujiwara Y;Kim CG;Cantor AB;Orkin SH
通讯作者：
Orkin SH
影响因子：
14.9
作者：
Forbes SA;Bindal N;Bamford S;Cole C;Kok CY;Beare D;Jia M;Shepherd R;Leung K;Menzies A;Teague JW;Campbell PJ;Stratton MR;Futreal PA
通讯作者：
Futreal PA
影响因子：
5.3
作者：
Faiola, F;Liu, XH;Martinez, E
通讯作者：
Martinez, E
影响因子：
45.3
作者：
Burnett, Alan K.;Hills, Robert K.;Wheatley, Keith
通讯作者：
Wheatley, Keith
影响因子：
20.3
作者：
Figueroa, Maria E.;Skrabanek, Lucy;Melnick, Ari
通讯作者：
Melnick, Ari