Differential regulation of the c-Myc/Lin28 axis discriminates subclasses of rearranged MLL leukemia.
Differential regulation of the c-Myc/Lin28 axis discriminates subclasses of rearranged MLL leukemia.
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DOI：
10.18632/oncotarget.8199
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发表时间：
2016-05-03
期刊：
影响因子：
--
通讯作者：
Muntean AG
中科院分区：
文献类型：
--
作者：
Chen L;Sun Y;Wang J;Jiang H;Muntean AG
MLL重排发生在骨髓和淋巴样白血病中，通常与预后不良相关，但这取决于融合伴侣。我们使用各种MLL融合蛋白（MLL-FP）在小鼠中模拟急性髓性白血病（AML），并观察到显著不同的生存结果。为了更好地理解这些白血病之间的差异，我们检查了用不同MLL-FP转化的白血病细胞的全基因组表达谱。RNA测序和途径分析将c-Myc转录程序确定为最显著的特征之一。c-Myc蛋白表达水平与急性髓系白血病潜伏期密切相关。在功能上，c-Myc的过表达导致MLL-FP细胞系中更积极的增殖速率。虽然所有MLL-FP转化的细胞显示出对BET抑制剂的敏感性，但高表达c-Myc的细胞显示出对Brd 4抑制的更大抗性。Myc靶标Lin 28 B在MLL-FP细胞系中也差异表达，与c-Myc表达一致。Lin 28 B miRNAs靶点的检测显示，let-7 g在白血病细胞中显著增加，与最长的疾病潜伏期相关，并且强制let-7 g表达诱导白血病原始细胞的分化。因此，不同MLL-FP对c-Myc/Lin 28/let-7 g程序的差异调节在功能上与MLL白血病中的疾病潜伏期和BET抑制剂抗性相关。
MLL rearrangements occur in myeloid and lymphoid leukemias and are generally associated with a poor prognosis, however this varies depending on the fusion partner. We modeled acute myeloid leukemia (AML) in mice using various MLL fusion proteins (MLL-FPs) and observed significantly different survival outcomes. To better understand the differences between these leukemias, we examined the genome wide expression profiles of leukemic cells transformed with different MLL-FPs. RNA-sequencing and pathway analysis identified the c-Myc transcriptional program as one of the top distinguishing features. c-Myc protein levels were highly correlative with AML disease latency in mice. Functionally, overexpression of c-Myc resulted in a more aggressive proliferation rate in MLL-FP cell lines. While all MLL-FP transformed cells displayed sensitivity to BET inhibitors, high c-Myc expressing cells showed greater resistance to Brd4 inhibition. The Myc target Lin28B was also differentially expressed in MLL-FP cell lines in agreement with c-Myc expression. Examination of Lin28B miRNAs targets revealed that let-7g was significantly increased in leukemic cells associated with the longest disease latency and forced let-7g expression induced differentiation of leukemic blasts. Thus, differential regulation of the c-Myc/Lin28/let-7g program by different MLL-FPs is functionally related to disease latency and BET inhibitor resistance in MLL leukemias.
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影响因子：
64.8
作者：
Lu, J;Getz, G;Golub, TR
通讯作者：
Golub, TR
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
3.7
作者：
Hebestreit K;Gröttrup S;Emden D;Veerkamp J;Ruckert C;Klein HU;Müller-Tidow C;Dugas M
通讯作者：
Dugas M
影响因子：
2.7
作者：
Falantes, Jose F.;Trujillo, Pablo;Perez-Simon, Jose A.
通讯作者：
Perez-Simon, Jose A.