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Global identification of MLL2-targeted loci reveals MLL2's role in diverse signaling pathways.

ABSTRACT: Myeloid/lymphoid or mixed-lineage leukemia (MLL)-family genes encode histone lysine methyltransferases that play important roles in epigenetic regulation of gene transcription. MLL genes are frequently mutated in human cancers. Unlike MLL1, MLL2 (also known as ALR/MLL4) and its homolog MLL3 are not well-understood. Specifically, little is known regarding the extent of global MLL2 involvement in the regulation of gene expression and the mechanism underlying its alterations in driving tumorigenesis. Here we profile the global loci targeted by MLL2. A combinatorial analysis of the MLL2 binding profile and gene expression in MLL2 wild-type versus MLL2-null isogenic cell lines identified direct transcriptional target genes and revealed the connection of MLL2 to multiple cellular signaling pathways, including the p53 pathway, cAMP-mediated signaling, and cholestasis signaling. In particular, we demonstrate that MLL2 participates in retinoic acid receptor signaling by promoting retinoic acid-responsive gene transcription. Our results present a genome-wide integrative analysis of the MLL2 target loci and suggest potential mechanisms underlying tumorigenesis driven by MLL2 alterations.

SUBMITTER: Guo C

PROVIDER: S-EPMC3491484 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Global identification of MLL2-targeted loci reveals MLL2's role in diverse signaling pathways.

Guo Changcun C Chang Chun-Chi CC Wortham Matthew M Chen Lee H LH Kernagis Dawn N DN Qin Xiaoxia X Cho Young-Wook YW Chi Jen-Tsan JT Grant Gerald A GA McLendon Roger E RE Yan Hai H Ge Kai K Papadopoulos Nickolas N Bigner Darell D DD He Yiping Y

Proceedings of the National Academy of Sciences of the United States of America 20121008 43

Myeloid/lymphoid or mixed-lineage leukemia (MLL)-family genes encode histone lysine methyltransferases that play important roles in epigenetic regulation of gene transcription. MLL genes are frequently mutated in human cancers. Unlike MLL1, MLL2 (also known as ALR/MLL4) and its homolog MLL3 are not well-understood. Specifically, little is known regarding the extent of global MLL2 involvement in the regulation of gene expression and the mechanism underlying its alterations in driving tumorigenesi ...[more]

PMID: 23045699

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Project description:BackgroundChordoma is a rare but devastating tumor that arises in the cranial skull base or spine. There are currently no US Food and Drug Administration-approved targeted therapies for chordoma, and little understanding of whether using more than one therapy has benefit over monotherapy.ObjectiveThe objective of this study was to systematically review the current status of clinical trials completed for patients with chordoma to determine if multimodal therapy offers a benefit in progression-free survival over monomodal therapy.MethodsWe performed a systematic review of the literature according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines to review the available clinical trials of targeted therapy for chordoma. We compiled the clinical data to determine if there is a benefit of multimodal therapy over monotherapy.ResultsOur search resulted in 11 clinical trials including 270 patients with advanced chordoma who were treated with targeted therapies. The most commonly employed targeted therapies acted within the following pathways: platelet-derived growth factor receptor (187 patients), vascular endothelial growth factor (66 patients), and mammalian target of rapamycin (43 patients). Reported progression-free survival for included studies ranged from 2.5 to 58 months, with the longest progression-free survival in a trial that included a platelet-derived growth factor receptor inhibitor, nilotinib, and concurrent radiotherapy (58.2 months). There was a higher range of progression-free survival for trials treating patients with multimodal therapy (10.2-14 months vs 2.5-9.2 months, except for a monotherapy trial published in 2020 with a progression-free survival of 18 months), and those published in 2018 or later (14-58.2 months vs 2.5-10.2 months). Only 23% of patients with chordoma in published clinical trials have been treated with multimodal therapy.ConclusionsProgression-free survival may be enhanced by the use of targeted therapy with concurrent radiotherapy, use of multimodal therapy, and use of newer targeted therapy. Future clinical trials should consider use of concurrent radiotherapy and multimodal therapy for patients with advanced chordoma.

Dataset Information

Global identification of MLL2-targeted loci reveals MLL2's role in diverse signaling pathways.

Publications

Global identification of MLL2-targeted loci reveals MLL2's role in diverse signaling pathways.

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