Transcriptional activation by MLL fusion proteins in leukemogenesis

Yokoyama, Akihiko

doi:10.1016/j.exphem.2016.10.014

Cited by 32 publications

(39 citation statements)

References 110 publications

(165 reference statements)

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“…However, we note that 12 of our patients have not been genotyped for MLL translocation. Nevertheless, this suggests that MLL translocations may induce a unique epigenetic state that dominates the overall enhancer landscape of the given AML sample, not surprising given the function of MLL fusion proteins in mis-regulating DOT1L function leading to aberrant histone H3K79 methylation (27). While mutations in NPM1 and FLT3 are enriched in clusters 2, 3, 4, and 6, no cluster-specific associations were observed for mutations in DNMT3A , TET2 , and IDH1 and IDH 2.…”

Section: Resultsmentioning

confidence: 99%

Superenhancer Analysis Defines Novel Epigenomic Subtypes of Non-APL AML, Including an RARα Dependency Targetable by SY-1425, a Potent and Selective RARα Agonist

McKeown¹,

Corces

Eaton³

et al. 2017

Cancer Discovery

121

153

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We characterized the enhancer landscape of 66 AML patients, identifying 6 novel subgroups and their associated regulatory loci. These subgroups are defined by their super-enhancer (SE) maps, orthogonal to somatic mutations, and are associated with distinct leukemic cell states. Examination of transcriptional drivers for these epigenomic subtypes uncovers a subset of patients with a particularly strong super-enhancer at the retinoic acid receptor alpha (RARA) gene locus. Presence of a RARA SE and concomitant high levels of RARA mRNA predisposes cell lines and ex vivo models to exquisite sensitivity to a selective agonist of RARα, SY-1425 (tamibarotene). Furthermore, only AML patient-derived xenograft (PDX) models with high RARA mRNA were found to respond to SY-1425. Mechanistically, we show that the response to SY-1425 in RARA-high AML cells is similar to that of APL treated with retinoids, characterized by the induction of known retinoic acid response genes, increased differentiation, and loss of proliferation.

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Section: Resultsmentioning

confidence: 99%

Superenhancer Analysis Defines Novel Epigenomic Subtypes of Non-APL AML, Including an RARα Dependency Targetable by SY-1425, a Potent and Selective RARα Agonist

McKeown¹,

Corces

Eaton³

et al. 2017

Cancer Discovery

121

153

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“…Loss of menin has been shown to coincide with the loss of H3K4me3 at specific genes, and at the same genes, gain of H3K27me3 that is an epigenetic mark of gene repression (Agarwal and Jothi 2012; Lin, et al 2015; Scacheri, et al 2006). MLL1 gene (chromosome 11q23) translocation with several different genes that encode transcription factors leads to the formation of MLL1-fusions that activate the expression of genes such as the HOX genes that cause leukemia (Yokoyama 2017). The interaction of menin in the Trithorax-like MLL protein complex has shown that menin is essential in this complex for the oncogenic activity of MLL1-fusion proteins to cause leukemia (Hughes, et al 2004; Yokoyama, et al 2005).…”

Section: An Unexpected Function Of Menin As a Pro-oncogenic Factor Inmentioning

confidence: 99%

The future: genetics advances in MEN1 therapeutic approaches and management strategies

Agarwal¹

2017

Endocrine-Related Cancer

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The identification of the multiple endocrine neoplasia type 1 (MEN1) gene in 1997 has shown that germline heterozygous mutations in the MEN1 gene located on chromosome 11q13, predisposes to the development of tumors in the MEN1 syndrome. Tumor development occurs upon loss of the remaining normal copy of the MEN1 gene in MEN1-target tissues. Therefore, MEN1 is a classic tumor suppressor gene in the context of MEN1. This tumor suppressor role of the protein encoded by the MEN1 gene, menin, holds true in mouse models with germline heterozygous Men1 loss wherein MEN1-associated tumors develop in adult mice after spontaneous loss of the remaining non-targeted copy of the Men1 gene. The availability of genetic testing for mutations in the MEN1 gene has become an essential part of the diagnosis and management of MEN1. Genetic testing is also helping to exclude mutation negative cases in MEN1 families from the burden of lifelong clinical screening. In the past 20 years, efforts of various groups world-wide have been directed at mutation analysis, molecular genetic studies, mouse models, gene expression studies, epigenetic regulation analysis, biochemical studies, and anti-tumor effects of candidate therapies in mouse models. This review will focus on the findings and advances from these studies to identify MEN1 germline and somatic mutations, the genetics of MEN1-related states, several protein partners of menin, the three-dimensional structure of menin, and menin-dependent target genes. The ongoing impact of all these studies on disease prediction, management and outcomes will continue in the years to come.

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“…Multiple studies reported that these alternations can affect transcriptional activity, resulting in cancer development 2 . Chromosomal abnormality also affects tumor malignancy, as these abnormalities frequently result in formation of fusion genes with TFs that activate oncogenic signaling pathways 3 …”

Section: Introductionmentioning

confidence: 99%

Targeting DNA binding proteins for cancer therapy

et al. 2020

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Yoshitomo Shiroma and Ryou-u Takahashi contributed equally to this work.Abbreviations: AEP, AF4 family/ENL family/P-TEFb; ARNT, aryl hydrocarbon receptor nuclear translocator; BRD4, bromodomain-containing protein 4; CBP, CREB-binding protein; DUX4, double homeobox protein 4; ETO, eight-twenty one; EWS, Ewing's sarcoma; FLI1, friend leukemia virus integration 1; HIF, hypoxia-inducible factor; MLL, mixed-lineage leukemia; SOX2, Sry-related high-mobility box 2; STAT3, signal transducer and activator of transcription 3; TF, transcription factor; TRF, telomere-repeat binding factor. AbstractDysregulation or mutation of DNA binding proteins such as transcription factors (TFs) is associated with the onset and progression of various types of disease, including cancer. Alteration of TF activity occurs in numerous cancer tissues due to gene amplification, deletion, and point mutations, and epigenetic modification. Although cancer-associated TFs are promising targets for cancer therapy, development of drugs targeting these TFs has historically been difficult due to the lack of high-throughput screening methods. Recent advances in technology for identification and selective inhibition of DNA binding proteins enable cancer researchers to develop novel therapeutics targeting cancer-associated TFs. In the present review, we summarize known cancer-associated TFs according to cancer type and introduce recently developed high-throughput approaches to identify selective inhibitors of cancer-associated TFs. K E Y W O R D SDNA binding protein, drug discovery, high-throughput screening, telomere, transcription factor | 1059 SHIROMA et Al.

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Transcriptional activation by MLL fusion proteins in leukemogenesis

Cited by 32 publications

References 110 publications

Superenhancer Analysis Defines Novel Epigenomic Subtypes of Non-APL AML, Including an RARα Dependency Targetable by SY-1425, a Potent and Selective RARα Agonist

Superenhancer Analysis Defines Novel Epigenomic Subtypes of Non-APL AML, Including an RARα Dependency Targetable by SY-1425, a Potent and Selective RARα Agonist

The future: genetics advances in MEN1 therapeutic approaches and management strategies

Targeting DNA binding proteins for cancer therapy

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