Zhou J, Wu J, Li B, Liu D, Yu J, Yan X, Zheng S, Wang J, Zhang L, Zhang L, He F, Li Q, Chen A, Zhang Y, Zhao X, Guan Y, Zhao X, Yan J, Ni J, Nobrega M A, Löwenberg B, Delwel R, Valk P J M, Kumar A, Xie L, Tenen D G, Huang G, Wang Q-F
Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, People's Republic of China.
1] Laboratory of Genome Variations and Precision Bio-Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, People's Republic of China [2] University of Chinese Academy of Sciences, Beijing, People's Republic of China [3] Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Leukemia. 2014 Jul;28(7):1436-48. doi: 10.1038/leu.2013.384. Epub 2013 Dec 26.
Mixed lineage leukemia (MLL) fusion proteins directly activate the expression of key downstream genes such as MEIS1, HOXA9 to drive an aggressive form of human leukemia. However, it is still poorly understood what additional transcriptional regulators, independent of the MLL fusion pathway, contribute to the development of MLL leukemia. Here we show that the transcription factor PU.1 is essential for MLL leukemia and is required for the growth of MLL leukemic cells via the promotion of cell-cycle progression and inhibition of apoptosis. Importantly, PU.1 expression is not under the control of MLL fusion proteins. We further identified a PU.1-governed 15-gene signature, which contains key regulators in the MEIS-HOX program (MEIS1, PBX3, FLT3, and c-KIT). PU.1 directly binds to the genomic loci of its target genes in vivo, and is required to maintain active expression of those genes in both normal hematopoietic stem and progenitor cells and in MLL leukemia. Finally, the clinical significance of the identified PU.1 signature was indicated by its ability to predict survival in acute myelogenous leukemia patients. Together, our findings demonstrate that PU.1 contributes to the development of MLL leukemia, partially via crosstalk with the MEIS/HOX pathway.
混合谱系白血病（MLL）融合蛋白直接激活关键下游基因如MEIS1、HOXA9的表达，从而引发侵袭性人类白血病。然而，目前对于独立于MLL融合途径的其他转录调节因子如何促进MLL白血病的发生仍知之甚少。在此，我们表明转录因子PU.1对MLL白血病至关重要，并且通过促进细胞周期进程和抑制细胞凋亡来维持MLL白血病细胞的生长。重要的是，PU.1的表达不受MLL融合蛋白的调控。我们进一步鉴定出一个由PU.1调控的15个基因的特征谱，其中包含MEIS-HOX程序中的关键调节因子（MEIS1、PBX3、FLT3和c-KIT）。PU.1在体内直接结合其靶基因的基因组位点，并且在正常造血干细胞和祖细胞以及MLL白血病中维持这些基因的活性表达均需要它。最后，所鉴定的PU.1特征谱能够预测急性髓性白血病患者的生存情况，这表明了其临床意义。总之，我们的研究结果表明，PU.1部分通过与MEIS/HOX途径相互作用，促进了MLL白血病的发生。
