Low expression of ASH2L protein correlates with a favorable outcome in acute myeloid leukemia

Butler, Jill Sergesketter; Qiu, Yi Hua; Zhang, Nianxiang; Yoo, Suk Young; Coombes, Kevin R.; Dent, Sharon Y.R.; Kornblau, Steven M.

doi:10.1080/10428194.2016.1235272

Cited by 24 publications

(20 citation statements)

References 49 publications

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“…In support of a potential role of ASH2L in tumor formation, ASH2L protein but not mRNA is overexpressed in the large majority of human tumors of different origin [ 121 , 122 ]. Consistent with these findings, low ASH2L expression correlates with a favorable prognosis in patients with acute myeloid leukemia [ 123 ]. Similarly, high expression of WDR5 , particularly when combined with high expression of MLL1 , is correlated with high-risk acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) [ 124 ].…”

Section: Kmt2 Complexes Are Essential For Development and Are Affesupporting

confidence: 54%

Modes of Interaction of KMT2 Histone H3 Lysine 4 Methyltransferase/COMPASS Complexes with Chromatin

Bochynska

Lüscher-Firzlaff

Lüscher

2018

Cells

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Regulation of gene expression is achieved by sequence-specific transcriptional regulators, which convey the information that is contained in the sequence of DNA into RNA polymerase activity. This is achieved by the recruitment of transcriptional co-factors. One of the consequences of co-factor recruitment is the control of specific properties of nucleosomes, the basic units of chromatin, and their protein components, the core histones. The main principles are to regulate the position and the characteristics of nucleosomes. The latter includes modulating the composition of core histones and their variants that are integrated into nucleosomes, and the post-translational modification of these histones referred to as histone marks. One of these marks is the methylation of lysine 4 of the core histone H3 (H3K4). While mono-methylation of H3K4 (H3K4me1) is located preferentially at active enhancers, tri-methylation (H3K4me3) is a mark found at open and potentially active promoters. Thus, H3K4 methylation is typically associated with gene transcription. The class 2 lysine methyltransferases (KMTs) are the main enzymes that methylate H3K4. KMT2 enzymes function in complexes that contain a necessary core complex composed of WDR5, RBBP5, ASH2L, and DPY30, the so-called WRAD complex. Here we discuss recent findings that try to elucidate the important question of how KMT2 complexes are recruited to specific sites on chromatin. This is embedded into short overviews of the biological functions of KMT2 complexes and the consequences of H3K4 methylation.

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Section: Kmt2 Complexes Are Essential For Development and Are Affesupporting

confidence: 54%

Modes of Interaction of KMT2 Histone H3 Lysine 4 Methyltransferase/COMPASS Complexes with Chromatin

Bochynska

Lüscher-Firzlaff

Lüscher

2018

Cells

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“…On the other hand, genetic mutations of the core subunits are rarely found in human cancers. Instead, the DPY30 (51), ASH2L (24,52), and WDR5 (25,53,54) core subunits have been found to be overexpressed in cancers, show correlation of high expression levels with poor prognosis, and, in some cases, functionally promote tumorigenesis. Such differential regulations and roles elicit interesting questions relating to the exact roles of these subunits and the associated H3K4 methylation in cancer and merit further investigation.…”

Section: Discussionmentioning

confidence: 99%

Hijacking a key chromatin modulator creates epigenetic vulnerability for MYC-driven cancer

Yang

Shah

Busby

et al. 2018

Journal of Clinical Investigation

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While the genomic binding of MYC protein correlates with active epigenetic marks on chromatin, it remains largely unclear how major epigenetic mechanisms functionally impact the tumorigenic potential of MYC. Here, we show that, compared with the catalytic subunits, the core subunits, including DPY30, of the major H3K4 methyltransferase complexes were frequently amplified in human cancers and selectively upregulated in Burkitt lymphoma. We show that DPY30 promoted the expression of endogenous MYC and was also functionally important for efficient binding of MYC to its genomic targets by regulating chromatin accessibility. Dpy30 heterozygosity did not affect normal animal physiology including lifespan, but significantly suppressed Myc-driven lymphomagenesis, as cells failed to combat oncogene-triggered apoptosis as a result of insufficient epigenetic modulation and expression of a subset of antiapoptotic genes. Dpy30 reduction also greatly impeded MYC-dependent cellular transformation, without affecting normal cell growth. These results suggest that MYC hijacks a major epigenetic pathway - H3K4 methylation - to facilitate its molecular activity in target binding and to coordinate its oncogenic program for efficient tumorigenesis, meanwhile creating "epigenetic vulnerability." DPY30 and the H3K4 methylation pathway are thus potential epigenetic targets for treating certain MYC-driven cancers.

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“…While studying the same population, high phosphorylation of serine 318-321 on FOXO3 was identified as an independent adverse prognostic factor [68] and low expression of ASH2L was related to poorer outcomes as well [69]. Other individual prognostic protein biomarkers that have been discovered in AML include LGALS3 [70], TGM2 [71], and FLI1 [72].…”

Section: Antibody-based Protein Microarraysmentioning

confidence: 99%

Targeted therapy in acute myeloid leukemia: current status and new insights from a proteomic perspective

Dijk

Bont

Kornblau

2020

Expert Review of Proteomics

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Introduction: The biological heterogeneity of acute myeloid leukemia (AML) complicates personalized medicine. Individual prognosis is typically based on the presence of chromosomal and genetic lesions. Nevertheless, these classifications often lack a priori information about response to therapy. Since the protein expression landscape reflects the functional activity state of cells, we hypothesize that analyzing this can be used for the identification of protein activity markers to provide better risk stratification as well as may provide targeted therapeutic guidance in AML. Areas covered: Herein, we review recently new adopted drugs in the treatment for AML and discuss how quantitative proteomic techniques may contribute to better therapeutic selection in AML. Expert commentary: The net functional state of the cell is defined by the activity of protein within all the pathways that are active in the cell. Recognition of the proteomic profile of the leukemic blast could, therefore, complement current classification systems by providing a better a priori description of what pathways are important within a cell as a guide to the selection of therapy for the patient.

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Low expression of ASH2L protein correlates with a favorable outcome in acute myeloid leukemia

Cited by 24 publications

References 49 publications

Modes of Interaction of KMT2 Histone H3 Lysine 4 Methyltransferase/COMPASS Complexes with Chromatin

Modes of Interaction of KMT2 Histone H3 Lysine 4 Methyltransferase/COMPASS Complexes with Chromatin

Hijacking a key chromatin modulator creates epigenetic vulnerability for MYC-driven cancer

Targeted therapy in acute myeloid leukemia: current status and new insights from a proteomic perspective

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