HOXA9 Cooperates with Activated JAK/STAT Signaling to Drive Leukemia Development
HOXA9 Cooperates with Activated JAK/STAT Signaling to Drive Leukemia Development
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DOI：
10.1158/2159-8290.cd-17-0583
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发表时间：
2018-05-01
期刊：
影响因子：
28.2
通讯作者：
Cools, Jan
中科院分区：
文献类型：
--
作者：
de Bock, Charles E.;Demeyer, Sofi E.;Cools, Jan
白血病是由造血前体细胞中多个基因组病变的积累引起的。然而，这些事件如何在致癌转化过程中合作仍然知之甚少。我们研究了激活的JAK 3/STAT 5信号传导和HOXA 9过表达之间的合作，这两个事件被确定为在T细胞急性淋巴细胞白血病中显著共同发生。突变体JAK 3和HOXA 9的表达导致起源于多能或淋巴定向祖细胞的白血病的快速发展，与单独的JAK 3或HOXA 9相比，疾病潜伏期显著降低。整合的RNA测序、染色质免疫沉淀测序和使用测序的转座酶可识别染色质测定（ATAC-seq）揭示了STAT 5和HOXA 9在整个基因组中具有共占据性，导致增强的STAT 5转录活性和FOS/JUN（AP 1）的异位激活。我们的数据表明，致癌的转录因子，如HOXA 9提供了一个肥沃的土壤，为特定的信号通路蓬勃发展，解释了为什么JAK/STAT途径突变积累在HOXA 9表达cells.SIGNIFICANCE：在癌症发展中的癌基因合作的机制仍然很差的特点。在这项研究中，我们模拟了T细胞白血病发展过程中激活的JAK/STAT信号传导和异位HOXA 9表达之间的合作。我们确定了STAT 5和HOXA 9在转录水平上的直接合作，并确定PIM 1激酶作为突变JAK/STAT/HOXA 9阳性白血病病例中可能的药物靶点。(C)2018年AACR。
Leukemia is caused by the accumulation of multiple genomic lesions in hematopoietic precursor cells. However, how these events cooperate during oncogenic transformation remains poorly understood. We studied the cooperation between activated JAK3/STAT5 signaling and HOXA9 overexpression, two events identified as significantly co-occurring in T-cell acute lymphoblastic leukemia. Expression of mutant JAK3 and HOXA9 led to a rapid development of leukemia originating from multipotent or lymphoid-committed progenitors, with a significant decrease in disease latency compared with JAK3 or HOXA9 alone. Integrated RNA sequencing, chromatin immunoprecipitation sequencing, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) revealed that STAT5 and HOXA9 have co-occupancy across the genome, resulting in enhanced STAT5 transcriptional activity and ectopic activation of FOS/JUN (AP1). Our data suggest that oncogenic transcription factors such as HOXA9 provide a fertile ground for specific signaling pathways to thrive, explaining why JAK/STAT pathway mutations accumulate in HOXA9-expressing cells.SIGNIFICANCE: The mechanism of oncogene cooperation in cancer development remains poorly characterized. In this study, we model the cooperation between activated JAK/STAT signaling and ectopic HOXA9 expression during T-cell leukemia development. We identify a direct cooperation between STAT5 and HOXA9 at the transcriptional level and identify PIM1 kinase as a possible drug target in mutant JAK/STAT/HOXA9-positive leukemia cases. (C) 2018 AACR.