Prognostic Importance of Histone Methyltransferase<i>MLL5</i>Expression in Acute Myeloid Leukemia

Damm, Frédérik; Oberacker, Tina; Thol, Felicitas; Surdziel, Ewa; Wagner, Katharina; Chaturvedi, Anuhar; Morgan, Michael; Bomm, Karoline; Göhring, Gudrun; Lübbert, Michael; Kanz, Lothar; Fiedler, Walter; Schlegelberger, Brigitte; Heil, Gerhard; Schlenk, Richard F.; Döhner, Konstanze; Döhner, Hartmut; Krauter, Jürgen; Ganser, Arnold; Heuser, Michael

doi:10.1200/jco.2010.31.1118

Cited by 46 publications

(37 citation statements)

References 46 publications

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“…Of note, patients with acquired ND4 mutations more often had concomitant DNMT3A mutations and lower MLL5 expression levels, which were described to have a negative influence on patient outcome. 5,22,29 Although our analysis may allow identification of DNMT3A mutated patients with favorable outcome, three of these patients were also classified as favorable risk and two as Intermediate-I risk using ELN criteria. The observation of unfavorable molecular markers (for example, DNMT3A mutations) in patients classified as ELN-favorable risk likely reflects the fact that AML results from the cooperation of several factors, and emphasizes the importance of discovering how interactions of these factors contribute to AML.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations/polymorphisms in the analyzed genes were used as categorical variables. To assess the impact of gene expression of MLL5, MN1, BAALC, ERG or WT1 on patient outcome, expression values were dichotomized (only for MLL5 quartiles were used 29 ) at the median expression value and used as categorical variables (median normalized copy number, gene transcripts per ABL transcripts). 31 For 34 de novo vs secondary AML, and ND4 mutation status.…”

Section: Discussionmentioning

confidence: 99%

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Prognostic implications and molecular associations of NADH dehydrogenase subunit 4 (ND4) mutations in acute myeloid leukemia

et al. 2011

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To study the prevalence and prognostic importance of mutations in NADH dehydrogenase subunit 4 (ND4), a mitochondrial encoded transmembrane component of the electron transport chain respiratory Complex I, 452 AML patients were examined for ND4 mutations by direct sequencing. The prognostic impact of ND4 mutations was evaluated in the context of other clinical prognostic markers and genetic risk factors. In all, 29 of 452 patients (6.4%) had either somatic (n ¼ 12) or germline (n ¼ 17) ND4 mutations predicted to affect translation. Somatic mutations were more likely to be heteroplasmic (Po0.001), to occur in predicted transmembrane domains (Po0.001) and were predicted to have damaging effects upon translation (Po0.001). Patients with somatically acquired ND4 mutations had significantly longer relapse-free survival (P ¼ 0.017) and overall survival (OS) (P ¼ 0.021) than ND4 wildtype patients. Multivariate analysis also demonstrated a tendency for increased survival in patients with somatic ND4 mutations (RFS: hazard ratio (HR) 0.25, confidence interval (CI) 0.06-1.01, P ¼ 0.052; OS: HR 0.29, CI 0.74-1.20, P ¼ 0.089). Somatic ND4 mutated patients had a higher prevalence of concomitant DNMT3A mutations (P ¼ 0.023) and a higher percentage of the NPM1/FLT3-ITD lowrisk genotype (P ¼ 0.021). Germline affected cases showed higher BAALC (P ¼ 0.036) and MLL5 (P ¼ 0.051) expression levels. Further studies are warranted to validate the favorable prognostic influence of acquired ND4 mutations in AML.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Prognostic implications and molecular associations of NADH dehydrogenase subunit 4 (ND4) mutations in acute myeloid leukemia

et al. 2011

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“…MLL5 has a different SET domain sequence and may function in a different manner from the rest of the MLL family (24). Acute myeloid leukemia patients with low MLL5 expression were found to have a worse outcome, when compared to patients with high transcript levels (25).…”

Section: Discussionmentioning

confidence: 99%

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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“…15 We identified 54 patients with CBF-AML and 153 patients with CN-AML in a previously published cohort of 344 patients, for whom global gene expression and promoter methylation data are available. [17][18][19] MLL5 expression levels of individual patients are represented by probe 223189_x_at and 223190_s_at from gene expression arrays (Online Supplementary Figure S9A).…”

Section: High Mll5 Expression Is Associated With Increased Dna Methylmentioning

confidence: 99%

“…15 To find out whether MLL5 expression levels affect decitabine response and DNA methylation in leukemia, we initiated the present study with decitabine-treated AML patients as well as transformed loss-of-Mll5 mouse bone marrow cells. Our study addresses the impact of MLL5 expression on outcome of decitabine-treated patients and establishes a link between MLL5 activity and DNA methylation levels.…”

Section: Introductionmentioning

confidence: 99%

Impact of MLL5 expression on decitabine efficacy and DNA methylation in acute myeloid leukemia

et al. 2014

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Methods Patients with decitabine administrationThis study included 57 patients (aged >60 years) with de novo or secondary AML (following MDS or treatment-related AML) who were treated in trial 00331 (registration n. DRKS00000069) with 135 mg/m 2 total decitabine infused intravenously over 72 h every six weeks 16 or who received 20 mg/m 2 per day (Days 1-5) every four weeks. Patients were included in the present study if RNA was available and if the sample contained at least 30% blasts (median 55%). Fifty samples (88%) were from bone marrow, 7 (12%) were from peripheral blood. Written informed consent was obtained according to the Declaration of Helsinki, and the study was approved by the local review boards of the participating centers. Quantification of MLL5 transcript levelsMLL5 expression levels were quantified using the TaqMan Gene Expression Assay (Assay ID: Hs00218773_m1, Applied Biosystems, Darmstadt, Germany) and the ABL FusionQuant Standard Kit as an endogenous control (Ipsogen, Marseille, France). A detailed description of the procedures can be found in the Online Supplementary Appendix.

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Prognostic Importance of Histone MethyltransferaseMLL5Expression in Acute Myeloid Leukemia

Abstract: High MLL5 expression levels are associated with a favorable outcome and may improve risk and treatment stratification in AML.

Cited by 46 publications

References 46 publications

Prognostic implications and molecular associations of NADH dehydrogenase subunit 4 (ND4) mutations in acute myeloid leukemia

Prognostic implications and molecular associations of NADH dehydrogenase subunit 4 (ND4) mutations in acute myeloid leukemia

Assessment of MLL methyltransferase gene expression in larynx carcinoma

Impact of MLL5 expression on decitabine efficacy and DNA methylation in acute myeloid leukemia

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