Trib1 promotes acute myeloid leukemia progression by modulating the transcriptional programs of Hoxa9

Abstract

The pseudokinase Trib1 functions as a myeloid oncogene that recruits the E3 ubiquitin ligase COP1 to C/EBPa and interacts with MEK1 to enhance ERK phosphorylation. Close genetic effect of Trib1 on Hoxa9 has been observed in myeloid leukemogenesis where Trib1 overexpression significantly accelerates Hoxa9-induced leukemia onset. However, the mechanism underlying how Trib1 functionally modulates Hoxa9 transcription activity is unclear. Herein, we provide evidence that Trib1 modulates Hoxa9-associated super-enhancers. ChIP-seq analysis identified increased histone H3K27Ac signals at super-enhancers of the Erg, Spns2, Rgl1, and Pik3cd loci, as well as increased mRNA expression of these genes. Modification of super-enhancer activity was mostly achieved via the degradation of C/EBPa p42 by Trib1, with a slight contribution from the MEK/ERK pathway. Silencing of Erg abrogated the growth advantage acquired by Trib1 overexpression, indicating that Erg is a critical downstream target of the Trib1/Hoxa9 axis. Moreover, treatment of acute myeloid leukemia (AML) cells with the BRD4 inhibitor JQ1 showed growth inhibition in a Trib1/Erg-dependent manner both in vitro and in vivo. Upregulation of ERG by TRIB1 was also observed in human AML cell lines, suggesting that Trib1 is a potential therapeutic target of Hoxa9-associated AML. Taken together, our study demonstrates a novel mechanism by which Trib1 modulates chromatin and Hoxa9-driven transcription in myeloid leukemogenesis.

Structure vs. Function of TRIB1—Myeloid Neoplasms and Beyond

“…Further investigation of this purported interaction is required, as similar results may be expected if mutation or loss of the MEK1-binding motif inhibits COP1 recruitment. It has also recently been shown that the degradation of C/EBPα is the primary mechanism through which TRIB1 drives AML progression, with a more minor contribution from MEK1/ERK activation [ 46 ].…”

“…A major role of TRIB1 and TRIB2 is to regulate levels of C/EBP family transcription factors [ 27 , 28 ], which are major upstream regulators of proliferation and differentiation of haematopoietic cells [ 54 , 55 , 56 , 57 ]. Both TRIB1 and TRIB2 have been implicated as oncogenes in AML, with the independent overexpression of both genes found sufficient to drive leukaemogenesis in mice [ 27 , 28 , 43 , 46 ]. Regulation of C/EBPs appears to be the fundamental mechanism behind this oncogenic capability.…”

“…TRIB1 overexpression is important in homeobox a9 (Hoxa9)/murine ecotropic virus integration site 1 (Meis1)-mediated AML [ 46 , 59 ]. In Hoxa9/Meis1-driven AML, Hoxa9 is able to bind DNA as a transcription factor and in complex with Meis1 drives unregulated gene expression promoting leukaemogenesis [ 8 , 46 , 59 ]. The cellular defence against Hoxa9/Meis1-driven reprogramming is the colocalisation of C/EBPα and Hoxa9, which prevents the formation of the Hoxa9/Meis1 complex, suppressing the Hoxa9/Meis1 transcriptional programme.…”

“…The cellular defence against Hoxa9/Meis1-driven reprogramming is the colocalisation of C/EBPα and Hoxa9, which prevents the formation of the Hoxa9/Meis1 complex, suppressing the Hoxa9/Meis1 transcriptional programme. The overexpression of TRIB1 leads to enhanced C/EBPα degradation, removing this suppression, allowing Meis1 to interact with Hoxa9, promoting unregulated transcription [ 8 , 46 , 59 ]. Co-operation between Hoxa9/Meis1 and TRIB1 overexpression drives a more aggressive AML than TRIB1 overexpression alone [ 59 ].…”

“…Co-operation between Hoxa9/Meis1 and TRIB1 overexpression drives a more aggressive AML than TRIB1 overexpression alone [ 59 ]. The degradation of C/EBPα not only allows the formation of the Hox9/Meis1 transcriptional complex, but also results in the modification of Hoxa9-associated super-enhancers, which further enhances the transformative transcriptional programme [ 46 ].…”