Combination Targeted Therapy to Disrupt Aberrant Oncogenic Signaling and Reverse Epigenetic Dysfunction in IDH2- and TET2-Mutant Acute Myeloid Leukemia.
Combination Targeted Therapy to Disrupt Aberrant Oncogenic Signaling and Reverse Epigenetic Dysfunction in IDH2- and TET2-Mutant Acute Myeloid Leukemia.
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DOI：
10.1158/2159-8290.cd-16-1049
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发表时间：
2017-05
期刊：
影响因子：
28.2
通讯作者：
Levine RL
中科院分区：
文献类型：
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作者：
Shih AH;Meydan C;Shank K;Garrett-Bakelman FE;Ward PS;Intlekofer AM;Nazir A;Stein EM;Knapp K;Glass J;Travins J;Straley K;Gliser C;Mason CE;Yen K;Thompson CB;Melnick A;Levine RL
急性髓性白血病（AML）的基因组研究已经确定了驱动DNA甲基化改变的突变，包括TET2和IDH2。本研究表明，由TET2或IDH2突变与FLT3ITD突变联合产生的aml模型分别对5-氮胞苷或IDH2抑制剂AG-221敏感。5-氮胞苷和AG-221处理诱导了异常DNA甲基化和转录输出的衰减，并导致白血病母细胞的减少，这与抗白血病活性一致。这些治疗益处与白血病细胞分化的恢复有关，造血功能的正常化来自突变细胞。相比之下，AG-221或5-氮杂胞苷联合FLT3抑制可减少突变等位基因负荷，从非突变的干细胞逐渐恢复正常造血，逆转失调的DNA甲基化和转录输出。总之，我们的研究表明，联合靶向信号通路和表观遗传通路可以增加AML的治疗反应。
Genomic studies in acute myeloid leukemias (AML) have identified mutations which drive altered DNA methylation, including TET2 and IDH2. Here we show that models of AMLs resulting from TET2 or IDH2 mutations combined with FLT3ITD mutations are sensitive to 5-Azacytidine or to the IDH2 inhibitor AG-221, respectively. 5-Azacytidine and AG-221 treatment induced an attenuation of aberrant DNA methylation and transcriptional output, and resulted in a reduction in leukemic blasts consistent with anti-leukemic activity. These therapeutic benefits were associated with restoration of leukemic cell differentiation, and the normalization of hematopoiesis was derived from mutant cells. By contrast, combining AG-221 or 5-Azacytidine with FLT3 inhibition resulted in a reduction in mutant allele burden, progressive recovery of normal hematopoiesis from non-mutant stem-progenitor cells, and reversal of dysregulated DNA methylation and transcriptional output. Together, our studies suggest combined targeting of signaling and epigenetic pathways can increase therapeutic response in AML.