Piribedil disrupts the MLL1-WDR5 interaction and sensitizes MLL-rearranged acute myeloid leukemia (AML) to doxorubicin-induced apoptosis

Zhang, Xiong; Zheng, Xingling; Yang, Hong; Yan, Juan; Fu, Xuhong; Wei, Rongrui; Xu, Xiaowei; Zhang, Zhuqing; Yu, Aisong; Zhou, Kaixin; Ding, Jian; Geng, Meiyu; Huang, Xun

doi:10.1016/j.canlet.2018.05.034

Cited by 22 publications

(28 citation statements)

References 42 publications

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“…Likewise, WIN site inhibitors appear to have different mechanisms of action across tumor types. Perhaps the best studied WRAD complex interaction is in MLL-rearranged AML, where one WIN site inhibitor led to global H3K4me2/3 reduction (Zhang et al, 2018), while another led to H3K4me3 reduction specifically on HOX genes (Cao et al, 2014). Yet another report found that WDR5 WIN site inhibitors led to potent induction of apoptosis in MLL1-rearranged AML by obstructing protein synthesis capacity, independently of changes in histone methylation (Aho et al, 2019a).…”

Section: Discussionmentioning

confidence: 99%

“…As a large peptidomimetic, MM-102 is limited to an in vitro setting and clearly lacks the properties needed (e.g., passive permeability, CNS penetration, metabolic stability) to fully study the impact of WDR5 WIN-site inhibition in the context of GBM. To identify more potent WRAD complex inhibitors for GBM, we leveraged previously described WRAD complex small molecule inhibitors tested in other cancers, including AML, neuroblastoma and pancreatic ductal adenocarcinoma (Aho et al, 2019a;Sun et al, 2015;Tian et al, 2020;Zhang et al, 2018). These included piribedil and OICR-9429, which have not been assessed in GBM or CSCs but displayed IC50s similar to those observed with MM-102 (Table 1).…”

Section: Reduction Of Csc Viability Growth and Self-renewal Via A Wdr5 Small Molecule Inhibitormentioning

confidence: 99%

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WDR5 represents a therapeutically exploitable target for cancer stem cells in glioblastoma

Mitchell

Shakya

Silver

et al. 2021

Preprint

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Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors that are driven by populations of cancer stem cells (CSCs). Despite their importance for tumor growth, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We employed spatially resolved loss-of-function screening in GBM patient-derived organoids to identify essential epigenetic regulators and identified WDR5 as indispensable for CSCs. WDR5 is a component of the WRAD complex, which promotes SET1-family-mediated Lys4 methylation of histone H3, associated with positive regulation of transcription. Genetic and pharmacologic inhibition of WDR5 reduced growth and self-renewal of CSCs as well as CSC-mediated tumor growth. Further, WDR5 inhibitors partially blocked WRAD complex assembly, reduced H3K4 trimethylation, and inhibited tumor growth. These findings highlight the role of WDR5 and the WRAD complex in CSCs for maintaining the CSC state and provide a rationale for therapeutic development of WRAD complex inhibitors for GBM and other advanced cancers.

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Section: Discussionmentioning

confidence: 99%

Section: Reduction Of Csc Viability Growth and Self-renewal Via A Wdr5 Small Molecule Inhibitormentioning

confidence: 99%

WDR5 represents a therapeutically exploitable target for cancer stem cells in glioblastoma

Mitchell

Shakya

Silver

et al. 2021

Preprint

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“…FBXW4 has six conserved WD repeat domains which are responsible for substrate binding. Drugs targeting another WD repeat domain-containing protein-WDR5-are available and exhibited strong tumor suppression ability in several human cancers including hematologic malignancies (33)(34)(35). Another drug (MLN4924, Pevonedistat), which can inhibit cellular cullin RING ubiquitin ligases, has also been tested as an anti-tumor drug in several clinical trials (36,37).…”

Section: Discussionmentioning

confidence: 99%

FBXW4 Is Highly Expressed and Associated With Poor Survival in Acute Myeloid Leukemia

et al. 2020

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The F-box and WD repeat domain-containing (FBXW) proteins play an important role in ubiquitin proteasome by inducing protein degradation. Ten FBXW proteins have been identified in humans. The functions of FBXW proteins, like FBXW7, have been well-established in many human cancers. However, little is known about their transcriptional expression profiles and relationship with prognosis in acute myeloid leukemia (AML). Here we investigated the roles of FBXW proteins in AML by analyzing their mRNA expression profiles and association with clinical features using data from EMBL-EBI, the Cancer Cell Line Encyclopedia, Gene Expression Profiling Interactive Analysis, and cBioPortal databases. Our results showed that the mRNA level of FBXW proteins were highly detected by microarray in 14 AML cell lines, although there were no obvious differences. The expression of FBXW4 was significantly higher in AML patients compared with that in normal controls (P < 0.01). Patients whose age was ≥60 years old had a higher FBXW4 expression when compared with those who were <60 years old (P < 0.05). Cytogenetic favorable-risk group patients had a much lower FBXW4 expression than the intermediate-and poor-risk group patients (P < 0.0001). Moreover, patients with high FBXW4 expression exhibited significantly shorter event-free survival (EFS) and overall survival (OS) than those with low FBXW4 expression (median EFS: 5.3 vs. 10.0 months, P = 0.025; median OS: 8.1 vs. 19.0 months, P= 0.015). A multivariate analysis indicated that high FBXW4 expression was an independent risk factor for poor EFS in AML patients who received intensive chemotherapy followed by allo-SCT. In summary, our data suggested that FBXW4 is aberrantly expressed in AML and high FBXW4 expression might be a poor prognostic biomarker; future functional and mechanistic studies will further illuminate the roles of FBXW4 in AML.

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“…The methylation of histone H3 lysine residues by HMTs has recently been found to be a potential target for cancer therapies. [31][32][33] For instance, the inhibition of EZH2, a specific methyltransferase for H3K27me3, can effectively suppress tumor growth by inducing cell-cycle arrest. 34 In particular, DOT1L, a specific methyltransferase for H3K79, plays a crucial role in tumor development and metastasis by mediating the transcription of its target genes.…”

Section: Discussionmentioning

confidence: 99%

Targeting Histone Methyltransferase DOT1L by a Novel Psammaplin A Analog Inhibits Growth and Metastasis of Triple-Negative Breast Cancer

Byun

Kim

Han

et al. 2019

Molecular Therapy - Oncolytics

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Triple-negative breast cancer (TNBC) is the most intractable cancer in women with a high risk of metastasis. While hyper-methylation of histone H3 catalyzed by disruptor of telomeric silencing 1-like (DOT1L), a specific methyltransferase for histone H3 at lysine residue 79 (H3K79), is reported as a potential target for TNBCs, early developed nucleoside-type DOT1L inhibitors are not sufficient for effective inhibition of growth and metastasis of TNBC cells. We found that TNBC cells had a high expression level of DOT1L and a low expression level of E-cadherin compared to normal breast epithelial cells and non-TNBC cells. Here, a novel psammaplin A analog (PsA-3091) exhibited a potent inhibitory effect of DOT1L-mediated H3K79 methylation. Consistently, PsA-3091 also significantly inhibited the proliferation, migration, and invasion of TNBC cells along with the augmented expression of E-cadherin and the suppression of N-cadherin, ZEB1, and vimentin expression. In an orthotopic mouse model, PsA-3091 effectively inhibited lung metastasis and tumor growth by the regulation of DOT1L activity and EMT biomarkers. Together, we report here a new template of DOT1L inhibitor and suggest that targeting DOT1L-mediated H3K79 methylation by a novel PsA analog may be a promising strategy for the treatment of metastatic breast cancer patients.

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Piribedil disrupts the MLL1-WDR5 interaction and sensitizes MLL-rearranged acute myeloid leukemia (AML) to doxorubicin-induced apoptosis

Cited by 22 publications

References 42 publications

WDR5 represents a therapeutically exploitable target for cancer stem cells in glioblastoma

WDR5 represents a therapeutically exploitable target for cancer stem cells in glioblastoma

FBXW4 Is Highly Expressed and Associated With Poor Survival in Acute Myeloid Leukemia

Targeting Histone Methyltransferase DOT1L by a Novel Psammaplin A Analog Inhibits Growth and Metastasis of Triple-Negative Breast Cancer

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