Abstract
Transcription factor MYB has recently emerged as a promising drug target for the treatment of acute myeloid leukemia (AML). Here, we have characterized a group of natural sesquiterpene lactones (STLs), previously shown to suppress MYB activity, for their potential to decrease AML cell proliferation. Unlike what was initially thought, these compounds inhibit MYB indirectly via its cooperation partner C/EBPβ. C/EBPβ-inhibitory STLs affect the expression of a large number of MYB-regulated genes, suggesting that the cooperation of MYB and C/EBPβ broadly shapes the transcriptional program of AML cells. We show that expression of GFI1, a direct MYB target gene, is controlled cooperatively by MYB, C/EBPβ, and co-activator p300, and is down-regulated by C/EBPβ-inhibitory STLs, exemplifying that they target the activity of composite MYB-C/EBPβ-p300 transcriptional modules. Ectopic expression of GFI1, a zinc-finger protein that is required for the maintenance of hematopoietic stem and progenitor cells, partially abrogated STL-induced myelomonocytic differentiation, implicating GFI1 as a relevant target of C/EBPβ-inhibitory STLs. Overall, our data identify C/EBPβ as a pro-leukemogenic factor in AML and suggest that targeting of C/EBPβ may have therapeutic potential against AML.
Highlights
We show that the growth factor independence 1 (GFI1) is a MYB-C/EBPβ-p300 target gene whose suppression by C/EBPβ-inhibitory sesquiterpene lactone (STL) contributes to their ability to inhibit the proliferation of leukemia cells
We have previously shown that several natural furanoheliangolide-type STLs possess MYB inhibitory activity in HD11-C3-GFP1 cells, a macrophage cell-line harboring a doxycycline-inducible MYB expression system and a stably integrated GFP reporter driven by the ciselements of the MYB-inducible chicken MIM1 gene [12, 29]
We confirmed the inhibition of C/EBPβ at the endogenous MRP126 gene, a physiological C/EBP target gene that is not expressed in fibroblasts but activated by exogenous C/EBPβ [34, 35] (Fig. 1C)
Summary
Recent progress in understanding its role in leukemia has made MYB a promising target for drug development [2]. Acute Myeloid Leukemia (AML) cells are “addicted” to high expression levels of MYB, making them more vulnerable to inhibition of MYB than normal HPCs [7,8,9,10]. This has further stimulated interest in MYB as a target for drug development as such a drug would allow the elimination of the leukemia cells while sparing normal hematopoiesis [2, 11]. Initial approaches based on small-molecule inhibitors of MYB have already yielded promising results, confirming that
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