GSE128570
Expression profiling by high throughput sequencing of THP-1 cells treated with AT or HA
Deregulation of transcription factor MYB contributes to the development of leukemia and other human cancers, making MYB an attractive target for drug development. We demonstrate that the natural sesquiterpene lactone (STL) 4,15-iso-atriplicolide tiglate (AT) is a novel potent inhibitor of MYB-dependent transcription. Further analysis revealed that C/EBPb, a transcription factor cooperating with MYB in myeloid cells, rather than MYB itself is inhibited by AT and related STLs. We show that these compounds induce apoptosis and differentiation in human acute myeloid leukemia (AML) cell lines and that ectopic expression of C/EBPbor of an activated version of MYB counteract these effects. Furthermore, gene expression profiling shows that AT as well as helenalin acetate, a compound previously shown to inhibit C/EBPb, affect the expression of a significant number of MYB-regulated genes although neither of these compounds targets MYB directly. Taken together these results suggest that C/EBPbp  lays a key role in AML cells by cooperating with MYB and supporting its activity. Finally, we show that AT inhibits primary murine and human AML patient cells in colony formation assays significantly stronger than normal hematopoietic progenitor cells. In summary, our work identifies several related STLs as novel potential drugs targeting AML and highlights a novel role of C/EBPbas a pro-leukemogenic factor in AML cells. We hypothesize that MYB and C/EBPbact together in a transcriptional module to maintain an undifferentiated state of AML cells and that targeting of this module via MYB or C/EBPbmay have therapeutic potential against AML. Overall design: Purpose: to reveal gene expression changes induced by AT or HA in THP-1 cells THP-1 cells were grown in the presence or absence of 1 µm AT or 0.5 µm HA for 24 hs. RNA profiling was obtained in triplicate using Illumina NextSeq