A tumor suppressive coactivator complex of p53 containing ASC-2 and histone H3-lysine-4 methyltransferase MLL3 or its paralogue MLL4

Lee, Jeongkyung; Kim, Dae Hwan; Lee, Seung‐Hee; Yang, Qi-En; Lee, Dong Kee; Lee, Soo-Kyung; Roeder, Robert G.; Lee, Jae Woo

doi:10.1073/pnas.0902873106

Cited by 192 publications

(213 citation statements)

References 42 publications

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“…H3K4 methylation is primarily localized in the promoter and regulatory regions of genes. Some transcription factors, such as Menin, LEDGF, HCF1/2, E2F, NFE2, p53, and c-Myb, have been shown to interact with MLL family members, which could lead to methylation of H3K4 in a locus-or DNA sequence-specific manner [16,17,[25][26][27][28][29]. A recent study by our group identified a physical and functional interaction between RUNX1 and MLL, and showed that both are required for maintenance of the H3K4me3 mark at two critical regulatory regions of the RUNX1 target gene PU.1 locus [30].…”

Section: Mll and Its Role In Normal Hematopoiesismentioning

confidence: 99%

Disordered epigenetic regulation in MLL-related leukemia

et al. 2012

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Leukemias bearing rearrangements of chromosome 11q23 are of particular interest due to their unique clinical and biological characteristics. 11q23 abnormalities occur in up to 70 % of infant leukemias, and about 10 % of adult acute myelogenous leukemias (AML). Two major rearrangements of the MLL gene are found in MLL-related leukemia. The most common of these is balanced translocations in which the N-terminal portion of MLL is fused to the C-terminus of the translocation partner. To date, nearly 100 different chromosome bands have been described in rearrangements involving MLL, and more than 70 known fusion partners of MLL have been cloned and characterized at the molecular level. Another major aberration of the MLL gene creates a repeat within the N-terminal MLL resulting in an internal partial tandem duplication (PTD). As a consequence, an extra amino-terminus is added in-frame to full-length MLL, resulting in leukemogenic MLL-PTD. MLL-PTD occurs predominantly in myeloid dysplasia syndromes, secondary AML (s-AML), and de novo AML. The presence of an MLL rearrangement generally confers a poor prognosis. MLL fusions and MLL-PTD are transcriptional regulators that take control of targets normally controlled by MLL, with the clustered HOX homeobox genes as prominent examples. Several epigenetic regulators that modify DNA or histones have been implicated in MLL fusion driven leukemogenesis, including DNA methylation, histone acetylation, and histone methylation. Recently, the histone methyltransferase DOT1L, the bromodomain and extra-terminal (BET) family member BRD4, and the MLL-interacting protein Menin have emerged as important mediators of MLL fusion-mediated leukemic transformation. The clinical development of targeted inhibitors of these epigenetic regulators has heralded promise for the treatment of MLL fusion leukemia. Although the biological function and molecular mechanism for MLL-PTD remains largely unknown, based on the primary protein structure of MLL-PTD and the knowledge gained so far from MLL fusions, newly developed inhibitors of epigenetic regulators could potentially also prove effective in the treatment of MLL-PTD related leukemias.

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Section: Mll and Its Role In Normal Hematopoiesismentioning

confidence: 99%

Disordered epigenetic regulation in MLL-related leukemia

et al. 2012

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“…PHD and SET domain proteins are chromatin regulators, and several are altered in cancer (Saha et al, 1995). Inactivation of MLL3 in mice results in epithelial tumor formation, suggesting that MLL3 functions as a tumor-suppressor gene (Lee et al 2009). In addition, MLL3 has been reported to be frequently deleted in myeloid leukemia (Ruault et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Association of MLL3 expression with prognosis in gastric cancer

Li¹,

Liu²,

Guo³

et al. 2014

Genet. Mol. Res.

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ABSTRACT. Low expression of myeloid/lymphoid or mixed-lineage leukemia 3 (MLL3) is reportedly associated with gastric cancer and tumor progression. The purpose of this study was to examine the expression of MLL3 in tissue samples of patients with gastric cancer and to analyze the relationship between MLL3 protein expression and clinical records. Using immunohistochemical staining and KaplanMeier analysis for MLL3 in gastric cancer patients, we found that low expression of MLL3 had a significant relationship with a low survival rate compared to positive MLL3 expression in the patients analyzed (P < 0.05). Our data suggest that MLL3 expression plays a vital role in gastric cancer development, and that this protein is an important marker for the prognosis of gastric cancer.

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“…This complex called ASCOM interacts with p53 and is required for expression of p53-target genes in response to DNA damage. These results indicate a role of MLL3 in the DNA damage response pathway through p53 activation (31). The down regulation of MLL3 in larynx cancer may therefore impair the DNA damage response contributing to the proliferation of cancer cells.…”

Section: Discussionmentioning

confidence: 83%

Assessment of MLL methyltransferase gene expression in larynx carcinoma

et al. 2015

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Abstract. Larynx cancer is the second most common type of cancer among all head and neck cancers. Deregulation of epigenetic effectors, including altered expression of histone methyltransferases from the MLL (mixed lineage leukemia) family, have been reported in many cancer types, yet little is known concerning their involvement in larynx cancer. Our objective was to determine the expression profile of MLL genes in larynx carcinoma and normal adjacent tissues and correlate this profile to tumor characteristics. We analyzed the expression profile of 5 MLL genes in 13 cases of larynx carcinoma and their adjacent non-tumor tissues using quantitative real-time PCR. MLL3 was significantly downregulated in tumor samples compared to their normal counterparts, and all MLL genes showed decreased expression in advanced tumors compared to tumors in the initial stage. Altered expression in a single MLL gene was associated with a similar alteration in the other MLL genes, revealing a strong correlation of expression in each individual patient. In conclusion, MLL genes may have similar transcriptional control, and decreased expression of these genes may contribute to larynx cancer progression. IntroductionLarynx cancer is the second most common among all head and neck cancers, representing 2% of all malignant diseases worldwide, with 140,000 cases occurring every year (1). In Brazil alone, there is an estimated risk of 7 cases for every 100,000 men. Usually, affected men are over the age of 40 years. The registered incidence of this cancer in women is very low, accounting for less than 1 case for every 100,000 women. The disease can cause hoarseness, dysphagia, odynophagia, pain and other symptoms, according to the affected site (supraglottis, glottis, subglottis). Early detection leads to a better prognosis, enabling a cure in the majority of the cases, while patients with advanced tumors usually succumb to the disease (2). Tobacco is the main associated risk factor, with a positive correlation of duration and intensity of smoking and increased risk for larynx cancer. Other risk factors include alcohol consumption, occupational exposures and various dietary habits. Moreover, the risk for larynx cancer increases with the combined effect of smoking and alcohol consumption (2). Studies concerning the association of human papillomavirus (HPV) infection with larynx cancer are heterogeneous and inconclusive, yet HPV infection appears to be associated with the risk of larynx cancer, particularly with the high-risk type HPV16 (3).Almost all cancers occurring in the head and neck are squamous cell carcinomas. Although they have the same histological characteristics, they appear to have genetic and epigenetic differences, depending on the site. Allelic loss leading to the loss of function of tumor-suppressor genes are an important alteration in larynx tumors, such as the loss of heterozygosity (LOH) at 9p21, a region harboring the cell cycle regulator p16 gene (4). LOH at 8p was also found to be common in larynx and oral squamous cell...

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A tumor suppressive coactivator complex of p53 containing ASC-2 and histone H3-lysine-4 methyltransferase MLL3 or its paralogue MLL4

Cited by 192 publications

References 42 publications

Disordered epigenetic regulation in MLL-related leukemia

Disordered epigenetic regulation in MLL-related leukemia

Association of MLL3 expression with prognosis in gastric cancer

Assessment of MLL methyltransferase gene expression in larynx carcinoma

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