BCOR Binding to MLL-AF9 Is Essential for Leukemia via Altered EYA1, SIX, and MYC Activity.
BCOR Binding to MLL-AF9 Is Essential for Leukemia via Altered EYA1, SIX, and MYC Activity.
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DOI：
10.1158/2643-3230.bcd-20-0036
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发表时间：
2020-07
影响因子：
11.2
通讯作者：
Charles Schmidt;N. Achille;Aravinda Kuntimaddi;Adam M. Boulton;B. Leach;Shubin Zhang;N. Zeleznik-Le;J. Bushweller
中科院分区：
文献类型：
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作者：
Charles Schmidt;N. Achille;Aravinda Kuntimaddi;Adam M. Boulton;B. Leach;Shubin Zhang;N. Zeleznik-Le;J. Bushweller
MLL是预后不良的急性白血病中染色体易位的靶点。常见的MLL融合伴侣AF 9（MLLT 3）可以直接结合AF 4、DOT 1 L、BCOR和CBX 8。为了描述BCOR和CBX 8与MLL-AF 9结合与白血病发生的相关性，在此我们确定了AF 9与CBX 8和BCOR的复合物的蛋白质结构，并表明所有四种伴侣与AF 9的结合是相互排斥的。使用结构分析，我们确定了选择性破坏AF 9与BCOR和CBX 8相互作用的点突变。在表达点突变型CBX 8或点突变型MLL-AF 9的骨髓干/祖细胞中，我们表明直接CBX 8/MLL-AF 9结合的破坏不会影响体外细胞增殖，而直接BCOR/MLL-AF 9结合的丧失会导致部分分化和增殖增加。引人注目的是，MLL-AF 9/BCOR结合的丧失消除了其在小鼠模型中的致白血病潜力。BCOR结合缺陷的MLL-AF 9突变体降低了EYA 1磷酸酶的表达和c-Myc的蛋白水平。BCOR与MLL-AF 9结合的减少改变了MYC驱动的基因表达程序，以及改变了SIX调节基因的表达，可能有助于观察到的白血病起始细胞群的减少。
MLL is a target of chromosomal translocations in acute leukemias with poor prognosis. The common MLL fusion partner AF9 (MLLT3) can directly bind to AF4, DOT1L, BCOR, and CBX8. To delineate the relevance of BCOR and CBX8 binding to MLL-AF9 for leukemogenesis, here we determine protein structures of AF9 complexes with CBX8 and BCOR, and show that binding of all four partners to AF9 is mutually exclusive. Using the structural analyses, we identify point mutations that selectively disrupt AF9 interactions with BCOR and CBX8. In bone marrow stem/progenitor cells expressing point mutant CBX8 or point mutant MLL-AF9, we show that disruption of direct CBX8/MLL-AF9 binding does not impact in vitro cell proliferation, whereas loss of direct BCOR/MLL-AF9 binding causes partial differentiation and increased proliferation. Strikingly, loss of MLL-AF9/BCOR binding abrogated its leukemogenic potential in a mouse model. The MLL-AF9 mutant deficient for BCOR binding reduces the expression of the EYA1 phosphatase and the protein level of c-Myc. Reduction in BCOR binding to MLL-AF9 alters a MYC-driven gene expression program, as well as altering expression of SIX-regulated genes, likely contributing to the observed reduction in the leukemia-initiating cell population.