The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
Sci Adv. 2019 Jul 10;5(7):eaaw4304. doi: 10.1126/sciadv.aaw4304. eCollection 2019 Jul.
The key myeloid transcription factor (TF), CEBPA, is frequently mutated in acute myeloid leukemia (AML), but the direct molecular effects of this leukemic driver mutation remain elusive. To investigate mutant AML, we performed microscale, in vivo chromatin immunoprecipitation sequencing and identified a set of aberrantly activated enhancers, exclusively occupied by the leukemia-associated CEBPA-p30 isoform. Comparing gene expression changes in human mutant AML and the corresponding mouse model, we identified , encoding CD73, as a cross-species AML gene with an upstream leukemic enhancer physically and functionally linked to the gene. Increased expression of CD73, mediated by the CEBPA-p30 isoform, sustained leukemic growth via the CD73/A2AR axis. Notably, targeting of this pathway enhanced survival of AML-transplanted mice. Our data thus indicate a first-in-class link between a cancer driver mutation in a TF and a druggable, direct transcriptional target.
关键的髓系转录因子（TF）CEBPA 在急性髓系白血病（AML）中经常发生突变，但这种白血病驱动突变的直接分子效应仍难以捉摸。为了研究突变的 AML，我们进行了微尺度、体内染色质免疫沉淀测序，并鉴定了一组异常激活的增强子，仅由白血病相关的 CEBPA-p30 同工型占据。在人类突变 AML 和相应的小鼠模型中比较基因表达变化，我们确定编码 CD73 的基因是一种跨物种 AML 基因，其上游白血病增强子在物理上和功能上与该基因相连。CEBPA-p30 同工型介导的 CD73 表达增加通过 CD73/A2AR 轴维持白血病的生长。值得注意的是，靶向该途径可提高 AML 移植小鼠的存活率。因此，我们的数据表明，TF 中的癌症驱动突变与可靶向的、直接的转录靶标之间存在首例此类关联。
