Pharmacological targeting of the Wdr5-MLL interaction in C/EBPα N-terminal leukemia

Abstract

The CEBPA gene is mutated in 9% of patients with acute myeloid leukemia (AML). Selective expression of a short 30 kDa C/EBPα translational isoform, termed p30, represents the most common type of CEBPA mutations in AML. The molecular mechanisms underlying p30-mediated transformation remain incompletely understood. We show that C/EBPα p30, but not the normal p42 isoform, preferentially interacts with Wdr5, a key component of SET/MLL histone-methyltransferase complexes. Accordingly, p30-bound genomic regions were enriched for MLL-dependent H3K4me3 marks. The p30-dependent increase in self-renewal and inhibition of myeloid differentiation required Wdr5, as its down-regulation inhibited proliferation and restored differentiation in p30-dependent AML models. OICR-9429 is a novel small-molecule antagonist of the Wdr5-MLL interaction. This compound selectively inhibited proliferation and induced differentiation in p30-expressing human AML cells. Our data reveal the mechanism of p30-dependent transformation and establish the essential p30-cofactor Wdr5 as a therapeutic target in CEBPA-mutant AML.

In Vivo Functional Platform Targeting Patient-Derived Xenografts Identifies WDR5-Myc Association as a Critical Determinant of Pancreatic Cancer

“…The findings of MLL being phosphorylated and activated by ATR in order to allow for full activation of the S-phase checkpoint further highlight the functional interplay between oncogene-induced DDR and COMPASS complex (Liu et al, 2010). Our preliminary experiments with two available low potency WDR5 inhibitors supported the centrality of the WDR5 network (OICR-9429), more than MLL-specific associations (MM-401), in driving PDAC cell proliferation, but also highlighted the requirement for a new generation of potent and selective Myc-oriented WDR5 inhibitors to deeply dissect the WDR5-Myc molecular dynamics and accelerate the bench-tobedside translation process (Grebien et al, 2015;Cao et al, 2014). In further support of our mechanistic findings, it was previously demonstrated that ATR inhibition sensitizes PDAC cell lines to radiation or chemotherapy (Prevo et al, 2012).…”

WDR5 Supports an N-Myc Transcriptional Complex That Drives a Protumorigenic Gene Expression Signature in Neuroblastoma

“…The small-molecule OICR9429 has recently been shown to block the interaction of WDR5 with MLL and its protein-protein interaction network (33). We performed protein coimmunoprecipitation assays and confirmed that treatment with OICR9429, compared with its negative control compound OICR0547, blocked the formation of WDR5-N-Myc protein complex (Supplementary Fig.…”

Long noncoding RNA BLACAT2 promotes bladder cancer–associated lymphangiogenesis and lymphatic metastasis

“…WDR5, a core component of the histone H3K4 methyltransferase complex, is crucial for vertebrate development and plays an important role in the self-renewal of pluripotent cells and cell differentiation (39,55). Multiple studies have recently documented that dysregulated WDR5 is involved in promoting cancer metastasis and chemoresistance (56,57), suggesting that WDR5 may serve as a therapeutic target for cancer (58). However, WDR5 is extensively expressed in numerous cell types and plays important roles in various biological functions (39,55,59,60).…”