RUNX1 is required for oncogenic Myb and Myc enhancer activity in T-cell acute lymphoblastic leukemia
RUNX1 is required for oncogenic Myb and Myc enhancer activity in T-cell acute lymphoblastic leukemia
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DOI：
10.1182/blood-2017-03-775536
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发表时间：
2017-10-12
期刊：
影响因子：
20.3
通讯作者：
Kelliher, Michelle A.
中科院分区：
文献类型：
--
作者：
Choi, AHyun;Illendula, Anuradha;Kelliher, Michelle A.
编码RUNX1转录因子的基因在t细胞急性淋巴细胞白血病（T-ALL）患者的一个亚群中发生突变，RUNX1突变与预后不良有关。这些突变聚集在dna结合的Runt结构域中，被认为代表了功能缺失突变，表明RUNX1抑制t细胞转化。RUNX1被认为在t细胞白血病同源盒1/3转化的人T-ALL细胞系和NOTCH1 T-ALL小鼠模型中具有肿瘤抑制作用。然而，逆转录病毒插入突变筛选发现RUNX基因在myc驱动的白血病小鼠模型中是协同致癌基因。为了阐明RUNX1在白血病发生中的功能，我们生成了Tal1/Lmo2/Rosa26-CreER T2 Runx1f/f小鼠，并检测了在载体或他莫昔芬存在下的白血病进展。我们发现Runx1缺失在体内抑制小鼠白血病生长，而RUNX沉默在人T-ALL细胞中引发细胞凋亡。我们证明了一种小分子抑制剂，旨在干扰CBFb与RUNX蛋白的结合，损害人类T-ALL细胞系和原发患者样本的生长。我们证明RUNX1缺陷改变了tal1和notch1调控基因的一个关键亚群的表达，分别包括MYB和MYC癌基因。这些研究提供了RUNX1具有致癌作用的遗传学和药理学证据，并揭示了RUNX1作为T-ALL治疗的新靶点。
The gene encoding the RUNX1 transcription factor is mutated in a subset of T-cell acute lymphoblastic leukemia (T-ALL) patients, and RUNX1 mutations are associated with a poor prognosis. These mutations cluster in the DNA-binding Runt domain and are thought to represent loss-of-function mutations, indicating that RUNX1 suppresses T-cell transformation. RUNX1 has been proposed to have tumor suppressor roles in T-cell leukemia homeobox 1/3-transformed human T-ALL cell lines and NOTCH1 T-ALL mouse models. Yet, retroviral insertional mutagenesis screens identify RUNX genes as collaborating oncogenes in MYC-driven leukemia mouse models. To elucidate RUNX1 function(s) in leukemogenesis, we generated Tal1/Lmo2/Rosa26-CreER T2 Runx1f/f mice and examined leukemia progression in the presence of vehicle or tamoxifen. We found that Runx1 deletion inhibits mouse leukemic growth in vivo and that RUNX silencing in human T-ALL cells triggers apoptosis. We demonstrate that a small molecule inhibitor, designed to interfere with CBFb binding to RUNX proteins, impairs the growth of human T-ALL cell lines and primary patient samples. We demonstrate that a RUNX1 deficiency alters the expression of a crucial subset of TAL1-and NOTCH1-regulated genes, including the MYB and MYC oncogenes, respectively. These studies provide genetic and pharmacologic evidence that RUNX1 has oncogenic roles and reveal RUNX1 as a novel therapeutic target in T-ALL.