Gene Summary

Gene:PRDM16; PR/SET domain 16
Aliases: MEL1, KMT8F, LVNC8, PFM13, CMD1LL
Summary:The reciprocal translocation t(1;3)(p36;q21) occurs in a subset of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). This gene is located near the 1p36.3 breakpoint and has been shown to be specifically expressed in the t(1:3)(p36,q21)-positive MDS/AML. The protein encoded by this gene is a zinc finger transcription factor and contains an N-terminal PR domain. The translocation results in the overexpression of a truncated version of this protein that lacks the PR domain, which may play an important role in the pathogenesis of MDS and AML. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:histone-lysine N-methyltransferase PRDM16
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
Show (22)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Oncogene Fusion Proteins
  • Transcriptome
  • Myelodysplastic Syndromes
  • Chromosome Aberrations
  • Single Nucleotide Polymorphism
  • Adolescents
  • Up-Regulation
  • Leukemic Gene Expression Regulation
  • PRDM16
  • MDS1 and EVI1 Complex Locus Protein
  • Chronic Myelogenous Leukemia
  • Gene Expression
  • Gene Expression Profiling
  • Cell Differentiation
  • Core Binding Factor Alpha 2 Subunit
  • Childhood Cancer
  • Biomarkers, Tumor
  • Proto-Oncogenes
  • DNA Methylation
  • Disease-Free Survival
  • Tissue Array Analysis
  • Histone-Lysine N-Methyltransferase
  • Transcription Factors
  • Karyotyping
  • Neoplasm Proteins
  • Epigenetics
  • Acute Myeloid Leukaemia
  • Messenger RNA
  • Chromosome Banding
  • Neoplastic Cell Transformation
  • Cancer Gene Expression Regulation
  • Leukemia, Myelomonocytic, Acute
  • Promoter Regions
  • Chromosome 1
  • Zinc Fingers
  • Signal Transduction
  • Leukaemia
  • Homeodomain Proteins
  • MicroRNAs
  • Cell Proliferation
  • DNA-Binding Proteins
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: PRDM16 (cancer-related)

Fei LR, Huang WJ, Wang Y, et al.
PRDM16 functions as a suppressor of lung adenocarcinoma metastasis.
J Exp Clin Cancer Res. 2019; 38(1):35 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The transcription factor PR domain containing 16 (PRDM16) is known to play a significant role in the determination and function of brown and beige fat. However, the role of PRDM16 in tumor biology has not been well addressed. Here we investigated the impact of PRDM16 on tumor growth and metastasis in lung cancer.
METHODS: UALCAN database, immunoblotting and immunohistochemistry analysis were used to assess PRDM16 expression in lung cancer patients. Kaplan-Meier plotter database was used to analyze the overall survival of patients with lung cancer stratified by PRDM16 expression. PRDM16 overexpression and knockdown experiments were conducted to assess the effects of PRDM16 on growth and metastasis in vitro and in vivo, and its molecular mechanism was investigated in lung adenocarcinoma cells by chromatin immunoprecipitation-sequencing (ChIP-Seq), real time-quantitative PCR (RT-qPCR), luciferase assay, xenograft models and rescue experiments.
RESULTS: PRDM16 was downregulated in lung adenocarcinomas, and its expression level correlated with key pathological characteristics and prognoses of lung adenocarcinoma patients. Overexpressing PRDM16 inhibited the epithelial-to-mesenchymal transition (EMT) of cancer cells both in vivo and in vitro by repressing the transcription of Mucin-4 (MUC4), one of the regulators of EMT in lung adenocarcinomas. Furthermore, deleting the PR domain from PRDM16 increased the transcriptional repression of MUC4 by exhibiting significant differences in histone modifications on its promoter.
CONCLUSIONS: Our findings demonstrate a critical interplay between transcriptional and epigenetic modifications during lung adenocarcinoma progression involving EMT of cancer cells and suggest that PRDM16 is a metastasis suppressor and potential therapeutic target for lung adenocarcinomas.

Tegeder I, Thiel K, Erkek S, et al.
Functional relevance of genes predicted to be affected by epigenetic alterations in atypical teratoid/rhabdoid tumors.
J Neurooncol. 2019; 141(1):43-55 [PubMed] Related Publications
PURPOSE: Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly arising in infants. Mutations of SWI/SNF chromatin remodeling complex members SMARCB1/INI1 or (rarely) SMARCA4/Brg1 are the sole recurrent genetic lesions. Epigenetic studies revealed a large number of genes predicted to be affected by differential histone modifications in ATRT, but the role of these genes in the biology of ATRT remains uncertain. We therefore aimed at exploring the role of these genes in the detrimental effects of SMARCB1-deficiency.
METHODS: The functional relevance of 1083 genes predicted to be affected by epigenetic alterations in ATRT was examined in vivo using a Drosophila melanogaster model of SMARCB1-deficiency. Human orthologues of genes whose knockdown modified the phenotype in the Gal4-UAS fly model were further examined in ATRT samples and SMARCB1-deficient rhabdoid tumor cells.
RESULTS: Knockdown of Snr1, the fly orthologue of SMARCB1, resulted in a lethal phenotype and epigenetic alterations in the fly model. The lethal phenotype was shifted to later stages of development upon additional siRNA knockdown of 89 of 1083 genes screened in vivo. These included TGF-beta receptor signaling pathway related genes, e.g. CG10348, the fly orthologue of transcriptional regulator PRDM16. Subsequently, PRDM16 was found to be over-expressed in ATRT samples and knockdown of PRDM16 in SMARCB1-deficient rhabdoid tumor cells reduced proliferation.
CONCLUSIONS: These results suggest that a subset of genes affected by differential histone modification in ATRT is involved in the detrimental effects of SMARCB1-deficiency and also relevant in the biology of ATRT.

Zhang H, Zhu L, Bai M, et al.
Exosomal circRNA derived from gastric tumor promotes white adipose browning by targeting the miR-133/PRDM16 pathway.
Int J Cancer. 2019; 144(10):2501-2515 [PubMed] Related Publications
Cancer-related cachexia is a metabolic syndrome characterized by a wasting disorder of adipose and skeletal muscle and is accompanied by body weight loss and systemic inflammation. The treatment options for cancer cachexia are limited, and the molecular mechanism remains poorly understood. Circular RNAs (circRNAs) are a novel family of endogenous noncoding RNAs that have been proposed to regulate gene expression in mammals. Exosomes are small vesicles derived from cells, and recent studies have shown that circRNAs are stable in exosomes. However, little is known about the biological role of circRNAs in exosomes. In our study, we showed that circRNAs in plasma exosomes have specific expression features in gastric cancer (GC), and ciRS-133 is linked with the browning of white adipose tissue (WAT) in GC patients. Exosomes derived from GC cells deliver ciRS-133 into preadipocytes, promoting the differentiation of preadipocytes into brown-like cells by activating PRDM16 and suppressing miR-133. Moreover, knockdown of ciRS-133 reduced cancer cachexia in tumor-implanted mice, decreasing oxygen consumption and heat production. Thus, exosome-delivered circRNAs are involved in WAT browning and play a key role in cancer-associated cachexia.

Sorrentino A, Federico A, Rienzo M, et al.
PR/SET Domain Family and Cancer: Novel Insights from the Cancer Genome Atlas.
Int J Mol Sci. 2018; 19(10) [PubMed] Free Access to Full Article Related Publications
The PR/SET domain gene family (PRDM) encodes 19 different transcription factors that share a subtype of the SET domain [Su(var)3-9, enhancer-of-zeste and trithorax] known as the PRDF1-RIZ (PR) homology domain. This domain, with its potential methyltransferase activity, is followed by a variable number of zinc-finger motifs, which likely mediate protein⁻protein, protein⁻RNA, or protein⁻DNA interactions. Intriguingly, almost all PRDM family members express different isoforms, which likely play opposite roles in oncogenesis. Remarkably, several studies have described alterations in most of the family members in malignancies. Here, to obtain a pan-cancer overview of the genomic and transcriptomic alterations of

Deng J, Kong W, Mou X, et al.
Identifying novel candidate biomarkers of RCC based on WGCNA analysis.
Per Med. 2018; 15(5):381-394 [PubMed] Related Publications
AIM: Extracting differential expression genes (DEGs) is an effective approach to improve the accuracy of determining the candidate biomarker genes. However, the previous DEGs analysis methods ignore that the expression levels of genes in different pathology stages of cancers are complex and various.
METHODS: In our study, staging DEGs analysis and weighted gene co-expression network analysis were applied to gene expression data of renal cell carcinoma (RCC).
RESULTS: According to construct gene topology network for exploring hub genes, 12 genes were identified as hub genes.
CONCLUSION: Combining with the effect of hub gene expression level on RCC patient survival and different biological data analysis, three hub genes were found that they might be three novel candidate biomarkers of RCC.

Bibi F, Ali I, Naseer MI, et al.
Detection of genetic alterations in gastric cancer patients from Saudi Arabia using comparative genomic hybridization (CGH).
PLoS One. 2018; 13(9):e0202576 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The present study was conducted to discover genetic imbalances such as DNA copy number variations (CNVs) associated with gastric cancer (GC) and to examine their association with different genes involved in the process of gastric carcinogenesis in Saudi population.
METHODS: Formalin-fixed paraffin-embedded (FFPE) tissues samples from 33 gastric cancer patients and 15 normal gastric samples were collected. Early and late stages GC samples were genotyped and CNVs were assessed by using Illumina HumanOmni1-Quad v.1.0 BeadChip.
RESULTS: Copy number gains were more frequent than losses throughout all GC samples compared to normal tissue samples. The mean number of the altered chromosome per case was 64 for gains and 40 for losses, and the median aberration length was 679115bp for gains and 375889bp for losses. We identified 7 high copy gain, 52 gains, 14 losses, 32 homozygous losses, and 10 copy neutral LOHs (loss of heterozygosities). Copy number gains were frequently detected at 1p36.32, 1q12, 1q22, 2p11.1, 4q23-q25, 5p12-p11, 6p21.33, 9q12-q21.11, 12q11-q12, 14q32.33, 16p13.3, 17p13.1, 17q25.3, 19q13.32, and losses at 1p36.23, 1p36.32, 1p32.1, 1q44, 3q25.2, 6p22.1, 6p21.33, 8p11.22, 10q22.1, 12p11.22, 14q32.12 and 16q24.2. We also identified 2 monosomy at chromosome 14 and 22, 52 partially trisomy and 22 whole chromosome 4 neutral loss of heterozygosities at 13q14.2-q21.33, 5p15.2-p15.1, 5q11.2-q13.2, 5q33.1-q34 and 3p14.2-q13.12. Furthermore, 11 gains and 2 losses at 1p36.32 were detected for 11 different GC samples and this region has not been reported before in other populations. Statistical analysis confirms significant association of H. pylori infection with T4 stage of GC as compare to control and other stages.
CONCLUSIONS: We found that high frequency of copy number gains and losses at 1p36.23, 1p32.1, 1p36.32, 3q25.2, 6p21.33 and 16q24.2 may be common events in gastric cancer. While novel CNVs at 1p36.32 harbouring PRDM16, TP73 and TP73-AS1 genes showed 11 gains and 2 losses for 11 different GC cases and this region is not reported yet in Database of Genomic Variants may be specific to Saudi population.

Lv W, Yu X, Li W, et al.
Low expression of LINC00982 and PRDM16 is associated with altered gene expression, damaged pathways and poor survival in lung adenocarcinoma.
Oncol Rep. 2018; 40(5):2698-2709 [PubMed] Related Publications
Recently, long non‑coding RNAs (lncRNAs) have been shown to play critical roles in lung adenocarcinoma (LUAD). The present study aimed to explore the effect of LINC00982 and PRDM16 on clinical features and survival in LUAD. We found that LUAD patients demonstrated lower expression and copy number variation but higher methylation of long intergenic non‑protein coding RNA 982 (LINC00982) and PR domain containing 16 (PRDM16) compared with controls. Thus, we divided the LUAD patients into two groups according to the median expression of LINC00982 and PRDM16. Through differential expression, KEGG pathway enrichment and Ingenuity® Pathway Analysis (IPA), we found that patients with low expression of both LINC00982 and PRDM16 presented with more deregulated genes, as well as more significant pathways, than patients with high expression of these two genes. In addition, Kaplan‑Meier curves and Cox proportional hazards models revealed that patients with low expression of LINC00982, PRDM16 or both, showed poorer survival than the groups with high expression of LINC00982, PRDM16. We further used multivariate survival models to verify these results. Furthermore, we confirmed that the expression of LINC00982 and PRDM16 was significantly decreased in LUAD cell lines compared to normal cell lines in vitro. In conclusion, the present study revealed that LINC00982 and PRDM16 may serve as biomarkers or potential drug targets for the diagnosis and therapy of LUAD.

Yang L, Zhang W, Wang Y, et al.
Hypoxia-induced miR-214 expression promotes tumour cell proliferation and migration by enhancing the Warburg effect in gastric carcinoma cells.
Cancer Lett. 2018; 414:44-56 [PubMed] Related Publications
miR-214 is an important oncomiRNA and is upregulated in various types of cancer, including gastric cancer. However, the molecular mechanism underlying the ectopic expression and function of miR-214 in gastric cancer is largely undefined. In this study, we found that miR-214 induces the Warburg effect and promotes the migration and proliferation of human gastric cancer cells. According to the mechanistic analysis, miR-214 expression is induced by environmental hypoxia, and miR-214 mediates hypoxia-induced functions. We then explored the molecular mechanism by which miR-214 enhances the Warburg effect in gastric cancer cells and identified the adenosine A2A receptor (A2AR) and PR/SET domain 16 (PRDM16) genes as the direct targets of miR-214. In conclusion, miR-214 inhibits A2AR and PRDM16 expression and enhances the Warburg effect in gastric cancer cells, thus promoting the proliferation and migration of gastric cancer cells. This study highlights an important role for the hypoxia-miR-214-PRDM16/A2AR pathway in the tumourigenesis of gastric cancer and may facilitate the development of new therapeutics against hypoxic tumours.

Cuppens T, Moisse M, Depreeuw J, et al.
Integrated genome analysis of uterine leiomyosarcoma to identify novel driver genes and targetable pathways.
Int J Cancer. 2018; 142(6):1230-1243 [PubMed] Related Publications
Uterine leiomyosarcomas (uLMS) are rare, aggressive malignancies for which limited treatment options are available. To gain novel molecular insights into uLMS and identify potential novel therapeutic targets, we characterized 84 uLMS samples for genome-wide somatic copy number alterations, mutations, gene fusions and gene expression and performed a data integration analysis. We found that alterations affecting TP53, RB1, PTEN, MED12, YWHAE and VIPR2 were present in the majority of uLMS. Pathway analyses additionally revealed that the PI3K/AKT/mTOR, estrogen-mediated S-phase entry and DNA damage response signaling pathways, for which inhibitors have already been developed and approved, frequently harbored genetic changes. Furthermore, a significant proportion of uLMS was characterized by amplifications and overexpression of known oncogenes (CCNE1, TDO2), as well as deletions and reduced expression of tumor suppressor genes (PTEN, PRDM16). Overall, it emerged that the most frequently affected gene in our uLMS samples was VIPR2 (96%). Interestingly, VIPR2 deletion also correlated with unfavorable survival in uLMS patients (multivariate analysis; HR = 4.5, CI = 1.4-14.3, p = 1.2E-02), while VIPR2 protein expression was reduced in uLMS vs. normal myometrium. Moreover, stimulation of VIPR2 with its natural agonist VIP decreased SK-UT-1 uLMS cell proliferation in a dose-dependent manner. These data suggest that VIPR2, which is a negative regulator of smooth muscle cell proliferation, might be a novel tumor suppressor gene in uLMS. Our work further highlights the importance of integrative molecular analyses, through which we were able to uncover the genes and pathways most frequently affected by somatic alterations in uLMS.

Berdasco M, Gómez A, Rubio MJ, et al.
DNA Methylomes Reveal Biological Networks Involved in Human Eye Development, Functions and Associated Disorders.
Sci Rep. 2017; 7(1):11762 [PubMed] Free Access to Full Article Related Publications
This work provides a comprehensive CpG methylation landscape of the different layers of the human eye that unveils the gene networks associated with their biological functions and how these are disrupted in common visual disorders. Herein, we firstly determined the role of CpG methylation in the regulation of ocular tissue-specification and described hypermethylation of retinal transcription factors (i.e., PAX6, RAX, SIX6) in a tissue-dependent manner. Second, we have characterized the DNA methylome of visual disorders linked to internal and external environmental factors. Main conclusions allow certifying that crucial pathways related to Wnt-MAPK signaling pathways or neuroinflammation are epigenetically controlled in the fibrotic disorders involved in retinal detachment, but results also reinforced the contribution of neurovascularization (ETS1, HES5, PRDM16) in diabetic retinopathy. Finally, we had studied the methylome in the most frequent intraocular tumors in adults and children (uveal melanoma and retinoblastoma, respectively). We observed that hypermethylation of tumor suppressor genes is a frequent event in ocular tumors, but also unmethylation is associated with tumorogenesis. Interestingly, unmethylation of the proto-oncogen RAB31 was a predictor of metastasis risk in uveal melanoma. Loss of methylation of the oncogenic mir-17-92 cluster was detected in primary tissues but also in blood from patients.

Yamato G, Yamaguchi H, Handa H, et al.
Clinical features and prognostic impact of PRDM16 expression in adult acute myeloid leukemia.
Genes Chromosomes Cancer. 2017; 56(11):800-809 [PubMed] Related Publications
High PRDM16 (also known as MEL1) expression is a representative marker of acute myeloid leukemia (AML) with NUP98-NSD1 and is a significant predictive marker for poor prognosis in pediatric AML. However, the clinical features of adult AML with PRDM16 expression remain unclear. PRDM16 is highly homologous to MDS1/EVI1, which is an alternatively spliced transcript of MECOM (also known as EVI1). We investigated PRDM16 expression in 151 AML patients, with 47 (31%) exhibiting high PRDM16 expression (PRDM16/ABL1 ratio ≥ 0.010). High PRDM16 expression significantly correlated with DNMT3A (43% vs. 15%, P < 0.001) and NPM1 (43% vs. 21%, P = 0.010) mutations and partial tandem duplication of KMT2A (22% vs. 1%, P < 0.001). Remarkably, high-PRDM16-expression patients were frequent in the noncomplete remission group (48% vs. 21%, P = 0.002). Overall survival (OS) was significantly worse in high-PRDM16-expression patients than in low-PRDM16-expression patients (5-year OS, 18% vs. 34%; P = 0.002). This trend was observed more clearly among patients aged <65 years (5-year OS, 21% vs. 50%; P = 0.001), particularly in FLT3-ITD-negative patients in the intermediate cytogenetic risk group (5-year OS, 25% vs. 59%; P = 0.009). These results suggest that high PRDM16 expression is a significant predictive marker for poor prognosis in adult AML patients, similar to pediatric AML patients.

Peng X, Xue H, Lü L, et al.
Accumulated promoter methylation as a potential biomarker for esophageal cancer.
Oncotarget. 2017; 8(1):679-691 [PubMed] Free Access to Full Article Related Publications
We performed a two-stage molecular epidemiological study to explore DNA methylation profiles for potential biomarkers of esophageal squamous cell carcinoma (ESCC) in a Chinese population. Infinium Methylation 450K BeadChip was used to identify genes with differentially methylated CpG sites. Sixteen candidate genes were validated by sequencing 1160 CpG sites in their promoter regions using the Illumina MiSeq platform. When excluding sites with negative changes, 10 genes (BNIP3, BRCA1, CCND1, CDKN2A, HTATIP2, ITGAV, NFKB1, PIK3R1, PRDM16 and PTX3) showed significantly different methylation levels among cancer lesions, remote normal-appearing tissues, and healthy controls. PRDM16 had the highest diagnostic value with the AUC (95% CI) of 0.988 (0.965-1.000), followed by PIK3R1, with the AUC (95% CI) of 0.969 (0.928-1.000). In addition, the methylation status was higher in patients with advanced cancer stages. These results indicate that aberrant DNA methylation may be a potential biomarker for the diagnosis of ESCC.

Zhu S, Xu Y, Song M, et al.
PRDM16 is associated with evasion of apoptosis by prostatic cancer cells according to RNA interference screening.
Mol Med Rep. 2016; 14(4):3357-61 [PubMed] Related Publications
Histone methylation, which is regulated by histone methyltransferases (HMTs) and histone demethylases (HDMs), has been indicated to be involved in a variety of diseases, particularly in cancer, including androgen‑independent prostate cancer (PCa). However, the functions of HMTs and HDTs in cancer have largely remained elusive. The present study, utilized an RNA interference screening using a lentiviral small hairpin (sh)RNA library to systematically elucidate the function of HMTs and HDTs in PCa cell growth and viability. Nine HMTs and HDTs, namely FBXO11, PRDM10, JMJD8, MLL, SETD4, JMJD7, PRMT2, MEN1 and PRDM16, were identified to affect DU145 cell viability, as indicated by an MTS assay subsequent to knockdown of the specific genes using shRNA pools. Furthermore, flow cytometric analysis and western blot analysis of apoptosis‑associated proteins indicated that PRDM16 has an anti‑apoptotic role in PCa cells. In addition, the spliced form, sPRDM16/MEL1S, was detected to be overexpressed in PCa cell lines. In conclusion, the present study indicated an important oncogenic role of sPRDM16/MEL1S in PCa and suggested that PRDM16 may represent a novel therapeutic target.

Mehrian-Shai R, Yalon M, Moshe I, et al.
Identification of genomic aberrations in hemangioblastoma by droplet digital PCR and SNP microarray highlights novel candidate genes and pathways for pathogenesis.
BMC Genomics. 2016; 17:56 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The genetic mechanisms underlying hemangioblastoma development are still largely unknown. We used high-resolution single nucleotide polymorphism microarrays and droplet digital PCR analysis to detect copy number variations (CNVs) in total of 45 hemangioblastoma tumors.
RESULTS: We identified 94 CNVs with a median of 18 CNVs per sample. The most frequently gained regions were on chromosomes 1 (p36.32) and 7 (p11.2). These regions contain the EGFR and PRDM16 genes. Recurrent losses were located at chromosome 12 (q24.13), which includes the gene PTPN11.
CONCLUSIONS: Our findings provide the first high-resolution genome-wide view of chromosomal changes in hemangioblastoma and identify 23 candidate genes: EGFR, PRDM16, PTPN11, HOXD11, HOXD13, FLT3, PTCH, FGFR1, FOXP1, GPC3, HOXC13, HOXC11, MKL1, CHEK2, IRF4, GPHN, IKZF1, RB1, HOXA9, and micro RNA, such as hsa-mir-196a-2 for hemangioblastoma pathogenesis. Furthermore, our data implicate that cell proliferation and angiogenesis promoting pathways may be involved in the molecular pathogenesis of hemangioblastoma.

Lei Q, Liu X, Fu H, et al.
miR-101 reverses hypomethylation of the PRDM16 promoter to disrupt mitochondrial function in astrocytoma cells.
Oncotarget. 2016; 7(4):5007-22 [PubMed] Free Access to Full Article Related Publications
Our previous report identified PR domain containing 16 (PRDM16), a member of the PR-domain gene family, as a new methylation associated gene in astrocytoma cells. This previous study also reported that miR-101 is a tumor suppressor in glioma. The present study confirms that PRDM16 is a hypomethylated gene that can be overexpressed in astrocytoma patients and demonstrates that the hypomethylation status of the PRDM16 promoter can predict poor prognoses for astrocytoma patients. The results reported herein show that PRDM16 was inhibited by miR-101 directly and also through epigenetic regulation. PRDM16 was confirmed as a new target of miR-101 and shown to be directly inhibited by miR-101. miR-101 also decreased the expression of PRDM16 by altering the methylation status of the PRDM16 promoter. miR-101 was associated with a decrease in the methylation-related histones H3K4me2 and H3K27me3 and an increase in H3K9me3 and H4K20me3 on the PRDM16 promoter. In addition, EZH2, EED and DNMT3A were identified as direct targets of miR-101, and miR-101 suppressed PRDM16 expression by targeting DNMT3A which decreases histone H3K27me3 and H3K4me2 at the PRDM16 core promoter. The results reported here demonstrate that miR-101 disrupted cellular mitochondrial function and induced cellular apoptosis via the mitochondrial pathway; for example, MMP and ATP levels decreased, while there was an increase in ADP/ATP ratios and ROS levels, levels of cleaved Caspase-9 and cleaved-PARP, the Bax/Bcl-2 ratios, and Smac release from the mitochondria to the cytoplasm. Knockdown of PRDM16 reversed the anti-apoptotic effect of miR-101 inhibition. In summary, miR-101 reversed the hypomethylation of the PRDM16 promoter which suppressed the expression of PRDM16, disrupted cellular mitochondrial function, and induced cellular apoptosis.

Shiba N, Ohki K, Kobayashi T, et al.
High PRDM16 expression identifies a prognostic subgroup of pediatric acute myeloid leukaemia correlated to FLT3-ITD, KMT2A-PTD, and NUP98-NSD1: the results of the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-05 trial.
Br J Haematol. 2016; 172(4):581-91 [PubMed] Related Publications
Recent reports described the NUP98-NSD1 fusion as an adverse prognostic marker for acute myeloid leukaemia (AML) and PRDM16 (also known as MEL1) as the representative overexpressed gene in patients harbouring NUP98-NSD1 fusion. PRDM16 gene expression levels were measured via real-time polymerase chain reaction in 369 paediatric patients with de novo AML, of whom 84 (23%) exhibited PRDM16 overexpression (PRDM16/ABL1 ratio ≥0·010). The frequencies of patients with high or low PRDM16 expression differed widely with respect to each genetic alteration, as follows: t(8;21), 4% vs. 96%, P < 0·001; inv(16), 0% vs. 100%, P < 0·001; KMT2A (also termed MLL)- partial tandem duplication, 100% vs. 0%, P < 0·001; NUP98-NSD1, 100% vs. 0%, P < 0·001. The overall survival (OS) and event-free survival (EFS) among PRDM16-overexpressing patients were significantly worse than in patients with low PRDM16 expression (3-year OS: 51% vs. 81%, P < 0·001, 3-year EFS: 32% vs. 64%, P < 0·001) irrespective of other cytogenetic alterations except for NPM1. PRDM16 gene expression was particularly useful for stratifying FLT3-internal tandem duplication-positive AML patients (3-year OS: high = 30% vs. low = 70%, P < 0·001). PRDM16 overexpression was highly recurrent in de novo paediatric AML patients with high/intermediate-risk cytogenetic profiles and was independently associated with an adverse outcome.

Dong S, Chen J
SUMOylation of sPRDM16 promotes the progression of acute myeloid leukemia.
BMC Cancer. 2015; 15:893 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: In addition to genetic and epigenetic alteration, post-translational modification of proteins plays a critical role in the initiation, progression and maturation of acute myeloid leukemia (AML).
METHODS: The SUMOylation site of sPRDM16 at K568 was mutated to arginine by site-directed mutagenesis. THP-1 acute myeloid leukemia cells were transduced with a lentivirus containing wild type or K568 mutant sPRDM16. Proliferation, self-renewal and differentiation of transduced THP-1 cells were analyzed both in vitro cell culture and in mouse xenografts. Gene expression profiles were analyzed by RNA-seq.
RESULTS: Overexpression of sPRDM16 promoted proliferation, enhanced self-renewal capacity, but inhibited differentiation of THP-1 acute myeloid leukemia cells. We further confirmed that K568 is a bona fide SUMOylation site on sPRDM16. Mutation of the sPRDM16 SUMOylation site at K568 partially abolished the capacity of sPRDM16 to promote proliferation and inhibit differentiation of acute myeloid leukemia cells both in vitro and in mouse xenografts. Furthermore, THP-1 cells overexpressing sPRDM16-K568R mutant exhibited a distinct gene expression profile from wild type sPRDM16 following incubation with PMA.
CONCLUSIONS: Our results suggest that K568 SUMOylation of sPRDM16 plays an important role in the progression of acute myeloid leukemia.

Singh R, Parveen M, Basgen JM, et al.
Increased Expression of Beige/Brown Adipose Markers from Host and Breast Cancer Cells Influence Xenograft Formation in Mice.
Mol Cancer Res. 2016; 14(1):78-92 [PubMed] Free Access to Full Article Related Publications
UNLABELLED: The initiation and progression of breast cancer is a complex process that is influenced by heterogeneous cell populations within the tumor microenvironment. Although adipocytes have been shown to promote breast cancer development, adipocyte characteristics involved in this process remain poorly understood. In this study, we demonstrate enrichment of beige/brown adipose markers, contributed from the host as well as tumor cells, in the xenografts from breast cancer cell lines. In addition to uncoupling protein-1 (UCP1) that is exclusively expressed in beige/brown adipocytes, gene expression for classical brown (MYF5, EVA1, and OPLAH) as well as beige (CD137/TNFRSF9 and TBX1) adipocyte markers was also elevated in the xenografts. Enrichment of beige/brown characteristics in the xenografts was independent of the site of implantation of the breast tumor cells. Early stages of xenografts showed an expansion of a subset of mammary cancer stem cells that expressed PRDM16, a master regulator of brown adipocyte differentiation. Depletion of UCP1(+) or Myf5(+) cells significantly reduced tumor development. There was increased COX2 (MT-CO2) expression, which is known to stimulate formation of beige adipocytes in early xenografts and treatment with a COX2 inhibitor (SC236) reduced tumor growth. In contrast, treatment with factors that induce brown adipocyte differentiation in vitro led to larger tumors in vivo. A panel of xenografts derived from established breast tumor cells as well as patient tumor tissues were generated that expressed key brown adipose tissue-related markers and contained cells that morphologically resembled brown adipocytes.
IMPLICATIONS: This is the first report demonstrating that beige/brown adipocyte characteristics could play an important role in breast tumor development and suggest a potential target for therapeutic drug design.

Nagano G, Ohno H, Oki K, et al.
Activation of classical brown adipocytes in the adult human perirenal depot is highly correlated with PRDM16-EHMT1 complex expression.
PLoS One. 2015; 10(3):e0122584 [PubMed] Free Access to Full Article Related Publications
Brown fat generates heat to protect against cold and obesity. Adrenergic stimulation activates the thermogenic program of brown adipocytes. Although the bioactivity of brown adipose tissue in adult humans had been assumed to very low, several studies using positron emission tomography-computed tomography (PET-CT) have detected bioactive brown adipose tissue in adult humans under cold exposure. In this study, we collected adipose tissues obtained from the perirenal regions of adult patients with pheochromocytoma (PHEO) or non-functioning adrenal tumors (NF). We demonstrated that perirenal brown adipocytes were activated in adult patients with PHEO. These cells had the molecular characteristics of classical brown fat rather than those of beige/brite fat. Expression of brown adipose tissue markers such as uncoupling protein 1 (UCP1) and cell death-inducing DFFA-like effector A (CIDEA) was highly correlated with the amounts of PRD1-BF-1-RIZ1 homologous domain-containing protein-16 (PRDM16) - euchromatic histone-lysine N-methyltransferase 1 (EHMT1) complex, the key transcriptional switch for brown fat development. These results provide novel insights into the reconstruction of human brown adipocytes and their therapeutic application against obesity and its complications such as type 2 diabetes.

Jo A, Mitani S, Shiba N, et al.
High expression of EVI1 and MEL1 is a compelling poor prognostic marker of pediatric AML.
Leukemia. 2015; 29(5):1076-83 [PubMed] Related Publications
EVI1 and MEL1 are homolog genes whose transcriptional activations by chromosomal translocations are known in small subsets of leukemia. From gene expression profiling data of 130 Japanese pediatric acute myeloid leukemia (AML) patients, we found that EVI1 and MEL1 were overexpressed in ~30% of patients without obvious translocations of these gene loci, and that their high expression was significantly associated with inferior survival. High EVI1 expression was detected mainly in myelomonocytic-lineage (designated as e-M4/M5 subtype) leukemia with MLL rearrangements and in megakaryocytic-lineage (designated as e-M7 subtype) leukemia, and its prognostic association was observed in the e-M4/M5 subtype but not in the e-M7 subtype. On the other hand, high MEL1 expression was detected in myelocytic-lineage (designated as e-M0/M1/M2 subtype) and e-M4/M5 subtype leukemia without MLL rearrangements, and its prognostic association was independent from the subtypes. Because of their subtype-dependent and mutually exclusive expression, a combined evaluation of their high expression enabled a clear distinction of patients with inferior survival (P<0.00001 in event-free survival (EFS) and overall survival (OS)). This association was confirmed by quantitative reverse transcription PCR analysis of an independent cohort of 81 patients (P=0.00017 in EFS, P=0.00028 in OS). We propose that the combined estimation of EVI1 and MEL1 expression will be an effective method to predict the prognosis of pediatric AML.

Yu H, Neale G, Zhang H, et al.
Downregulation of Prdm16 mRNA is a specific antileukemic mechanism during HOXB4-mediated HSC expansion in vivo.
Blood. 2014; 124(11):1737-47 [PubMed] Free Access to Full Article Related Publications
Overexpression of HOXB4 in hematopoietic stem cells (HSCs) leads to increased self-renewal without causing hematopoietic malignancies in transplanted mice. The molecular basis of HOXB4-mediated benign HSC expansion in vivo is not well understood. To gain further insight into the molecular events underlying HOXB4-mediated HSC expansion, we analyzed gene expression changes at multiple time points in Lin(-)Sca1(+)c-kit(+) cells from mice transplanted with bone marrow cells transduced with a MSCV-HOXB4-ires-YFP vector. A distinct HOXB4 transcriptional program was reproducibly induced and stabilized by 12 weeks after transplant. Dynamic expression changes were observed in genes critical for HSC self-renewal as well as in genes involved in myeloid and B-cell differentiation. Prdm16, a transcription factor associated with human acute myeloid leukemia, was markedly repressed by HOXB4 but upregulated by HOXA9 and HOXA10, suggesting that Prdm16 downregulation was involved in preventing leukemia in HOXB4 transplanted mice. Functional evidence to support this mechanism was obtained by enforcing coexpression of sPrdm16 and HOXB4, which led to enhanced self-renewal, myeloid expansion, and leukemia. Altogether, these studies define the transcriptional pathways involved in HOXB4 HSC expansion in vivo and identify repression of Prdm16 transcription as a mechanism by which expanding HSCs avoid leukemic transformation.

Tan SX, Hu RC, Liu JJ, et al.
Methylation of PRDM2, PRDM5 and PRDM16 genes in lung cancer cells.
Int J Clin Exp Pathol. 2014; 7(5):2305-11 [PubMed] Free Access to Full Article Related Publications
AIMS: To investigate the changes of expression and methylation status of PRDM2, PRDM5, PRDM16 in lung cancer cells after treatment with demethylation agent.
METHODS: A549 (lung adenocarcinoma cell line), HTB-182 (lung squamous cell carcinoma cell line) and HBE (normal bronchial cell line) were treated with 5-aza-2dC. The methylation state of PRDM2, PRDM5, PRDM16 was detected by MSP. The expression of PRDM2, PRDM5, PRDM16 was detected by RT-PCR and Western blot analysis. Cell growth was detected by MTT assay.
RESULTS: 5-aza-2-dC reduced the methylation of PRDM2, PRDM5, PRDM16 gene in A549 and HTB-182 cells but not in HBE cells. Consistently, 5-aza-2dC increased mRNA and protein expression of PRDM2, PRDM5, PRDM16 in A549 and HTB-182 cells but not in HBE cells. Furthermore, 5-aza-2dC inhibited the growth of A549 and HTB-182 cells but not HBE cells.
CONCLUSIONS: PRDM2, PRDM5, PRDM16 promoters are methylated and their expression is suppressed in lung cancer cells. Demethylation drug 5-aza-2dC could upregulate the expression of PRDM2, PRDM5, PRDM16 and suppress lung cancer cell growth. 5-aza-2dC has potential to be used for lung cancer therapy by epigenetic mechanism.

Burghel GJ, Lin WY, Whitehouse H, et al.
Identification of candidate driver genes in common focal chromosomal aberrations of microsatellite stable colorectal cancer.
PLoS One. 2013; 8(12):e83859 [PubMed] Free Access to Full Article Related Publications
Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. Chromosomal instability (CIN) is a major driving force of microsatellite stable (MSS) sporadic CRC. CIN tumours are characterised by a large number of somatic chromosomal copy number aberrations (SCNA) that frequently affect oncogenes and tumour suppressor genes. The main aim of this work was to identify novel candidate CRC driver genes affected by recurrent and focal SCNA. High resolution genome-wide comparative genome hybridisation (CGH) arrays were used to compare tumour and normal DNA for 53 sporadic CRC cases. Context corrected common aberration (COCA) analysis and custom algorithms identified 64 deletions and 32 gains of focal minimal common regions (FMCR) at high frequency (>10%). Comparison of these FMCR with published genomic profiles from CRC revealed common overlap (42.2% of deletions and 34.4% of copy gains). Pathway analysis showed that apoptosis and p53 signalling pathways were commonly affected by deleted FMCR, and MAPK and potassium channel pathways by gains of FMCR. Candidate tumour suppressor genes in deleted FMCR included RASSF3, IFNAR1, IFNAR2 and NFKBIA and candidate oncogenes in gained FMCR included PRDM16, TNS1, RPA3 and KCNMA1. In conclusion, this study confirms some previously identified aberrations in MSS CRC and provides in silico evidence for some novel candidate driver genes.

Zhou Z, Darwal MA, Cheng EA, et al.
Cellular reprogramming into a brown adipose tissue-like phenotype by co-expression of HB-EGF and ADAM 12S.
Growth Factors. 2013; 31(6):185-98 [PubMed] Related Publications
Abnormal adipogenesis leads to excessive fat accumulation and several health disorders. Mouse fibroblasts (MLC) transfected with ADAM 12S and HB-EGF promoted lipid accumulation. Addition of KBR-7785, an ADAM 12S inhibitor, to HB-EGF/ADAM 12S expressing cells suppressed adipogenesis. BrdU incorporation was attenuated and enhanced mitotracker staining was observed in HB-EGF/ADAM 12S cells. Quantitative real time RT-PCR resulted in elevated levels of expression of three brown adipose tissue (BAT) genes (PRDM16, PGC-1α, and UCP-1), while expression levels of the three white adipose tissue (WAT) genes (PPARγ, C/EBPα, and AKT-1) were unaltered in HB-EGF/ADAM 12S cells. Amino- or carboxy-terminal deletions of HB-EGF (HB-EGFΔN and HB-EGFΔC) co-expressed with ADAM 12S stimulated lipid accumulation. Human epidermoid carcinoma cells (A431) also exhibited lipid accumulation by HB-EGF/ADAM 12S co-expression. These studies suggest ADAM 12S and HB-EGF are involved in cellular plasticity resulting in the production of BAT-like cells and offers insight into novel therapeutic approaches for fighting obesity.

Jiang MM, Gao L, Jing Y, et al.
Rapid detection of AML1 associated fusion genes in patients with adult acute myeloid leukemia and its clinical significance.
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2013; 21(4):821-9 [PubMed] Related Publications
This study was aimed to detect the expression of AML1 fusion genes in the patients with adult acute myeloid leukemia (AML) and further to investigate their association with the progression and prognosis of AML. Bone marrow samples were collected from 168 patients with de novo adult AML, and the expression of AML1 ETO, AML1-EVI1, AML1-MDS1, AML1-MTG16, AML1-PRDM16, AML1-LRP16, AML1-CLCA2 and AML1-PRDX4 was analyzed by a novel multiplex nested RT-PCR. Positive samples and minimal residual disease were further examined by real-time fluorescent quantitative PCR. The results showed that the AML1 fusion genes were found in 10.7% (18/168) patients. Among them, AML1-ETO in 12 (7.1%) cases were detected, AML1-EVI1 in 2 cases (1.2%), and AML1-MDS1, AML1-MTG16, AML1-PRDM16, and AML1-CLCA2 in 1 case (0.6%) each were detected. Among the patients with AML1-ETO, 10 patients (10/12, 83.33%) achieved complete remission (CR) after one cycle of chemotherapy, while 2 patients achieved CR after 2 cycles of chemotherapy. The 2 patients with AML1-EVI1 failed to achieve CR after one cycle of chemotherapy. Patients with AML1-MDS1, AML1-MTG16, AML1-PRDM16, or AML1-CACL2 did not achieve CR after one cycle of chemotherapy. It is concluded that AML1 fusion genes are more frequent and can provide the molecular markers for diagnostics and prognosis evaluation of AML and for monitoring MRD.

Frontini A, Vitali A, Perugini J, et al.
White-to-brown transdifferentiation of omental adipocytes in patients affected by pheochromocytoma.
Biochim Biophys Acta. 2013; 1831(5):950-9 [PubMed] Related Publications
In all mammals, white adipose tissue (WAT) and brown adipose tissue (BAT) are found together in several fat depots, forming a multi-depot organ. Adrenergic stimulation induces an increase in BAT usually referred to as "browning". This phenomenon is important because of its potential use in curbing obesity and related disorders; thus, understanding its cellular mechanisms in humans may be useful for the development of new therapeutic strategies. Data in rodents have supported the direct transformation of white into brown adipocytes. Biopsies of pure white omental fat were collected from 12 patients affected by the catecholamine-secreting tumor pheochromocytoma (pheo-patients) and compared with biopsies from controls. Half of the omental fat samples from pheo-patients contained uncoupling protein 1 (UCP1)-immunoreactive-(ir) multilocular cells that were often arranged in a BAT-like pattern endowed with noradrenergic fibers and dense capillary network. Many UCP1-ir adipocytes showed the characteristic morphology of paucilocular cells, which we have been described as cytological marker of transdifferentiation. Electron microscopy showed increased mitochondrial density in multi- and paucilocular cells and disclosed the presence of perivascular brown adipocyte precursors. Brown fat genes, such as UCP1, PR domain containing 16 (PRDM16) and β3-adrenoreceptor, were highly expressed in the omentum of pheo-patients and in those cases without visible morphologic re-arrangement. Of note, the brown determinant PRDM16 was detected by immunohistochemistry only in nuclei of multi- and paucilocular adipocytes. Quantitative electron microscopy and immunohistochemistry for Ki67 suggest an unlikely contribution of proliferative events to the phenomenon. The data support the idea that, in adult humans, white adipocytes of pure white fat that are subjected to adrenergic stimulation are able to undergo a process of direct transformation into brown adipocytes. This article is part of a Special Issue entitled Brown and White Fat: From Signaling to Disease.

Chen J, Chen Y, Chen Z
MiR-125a/b regulates the activation of cancer stem cells in paclitaxel-resistant colon cancer.
Cancer Invest. 2013; 31(1):17-23 [PubMed] Related Publications
In this study, we investigated ALDH1A3, Mcl1, and miR-125a/b expression in HT29 cells and the effect of miR-125a/b on ALDH1A3 and Mcl1 expression. Our results showed that low expression of miR-125a/b and high expression of ALDH1A3 and Mel1 were observed in both ALDH1-positive HT29 and HT29-taxol cells. Overexpression of miR-125a/b significantly inhibited ALDH1A3 and Mcl1 expression, reduced cell survival, and increased cell apoptosis in HT29-taxol cells. Injection of miR-125a/b expression vector inhibited tumor growth in xenograft HT29-taxol mouse model. The current study suggested that miR-125a/b expression plays a key role in chemoresistance through upregulating ALDH1A3 and Mcl1 gene expression.

Yang JJ, Cho SY, Suh JT, et al.
Detection of RUNX1-MECOM fusion gene and t(3;21) in a very elderly patient having acute myeloid leukemia with myelodysplasia-related changes.
Ann Lab Med. 2012; 32(5):362-5 [PubMed] Free Access to Full Article Related Publications
An 87-yr-old woman was diagnosed with AML with myelodysplasia-related changes (AML-MRC). The initial complete blood count showed Hb level of 5.9 g/dL, platelet counts of 27 × 10(9)/L, and white blood cell counts of 85.33 × 10(9)/L with 55% blasts. Peripheral blood samples were used in all the tests, as bone marrow examination could not be performed because of the patient's extremely advanced age and poor general health condition. Flow cytometric analysis, chromosome analysis, FISH, and reverse transcriptase-PCR (RT-PCR) results indicated AML-MRC resulting from t(3;21) with the RUNX1-MECOM fusion gene. To our knowledge, this is the second most elderly de novo AML patient associated with t(3;21) to be reported.

Wolf S, Rudolph C, Morgan M, et al.
Selection for Evi1 activation in myelomonocytic leukemia induced by hyperactive signaling through wild-type NRas.
Oncogene. 2013; 32(25):3028-38 [PubMed] Related Publications
Activation of NRas signaling is frequently found in human myeloid leukemia and can be induced by activating mutations as well as by mutations in receptors or signaling molecules upstream of NRas. To study NRas-induced leukemogenesis, we retrovirally overexpressed wild-type NRas in a murine bone marrow transplantation (BMT) model in C57BL/6J mice. Overexpression of wild-type NRas caused myelomonocytic leukemias ∼3 months after BMT in the majority of mice. A subset of mice (30%) developed malignant histiocytosis similar to mice that received mutationally activated NRas(G12D)-expressing bone marrow. Aberrant Ras signaling was demonstrated in cells expressing mutationally active or wild-type NRas, as increased activation of Erk and Akt was observed in both models. However, more NRas(G12D) were found to be in the activated, GTP-bound state in comparison with wild-type NRas. Consistent with observations reported for primary human myelomonocytic leukemia cells, Stat5 activation was also detected in murine leukemic cells. Furthermore, clonal evolution was detected in NRas wild-type-induced leukemias, including expansion of clones containing activating vector insertions in known oncogenes, such as Evi1 and Prdm16. In vitro cooperation of NRas and Evi1 improved long-term expansion of primary murine bone marrow cells. Evi1-positive cells upregulated Bcl-2 and may, therefore, provide anti-apoptotic signals that collaborate with the NRas-induced proliferative effects. As activation of Evi1 has been shown to coincide with NRAS mutations in human acute myeloid leukemia, our murine model recapitulates crucial events in human leukemogenesis.

Adair JE, Beard BC, Trobridge GD, et al.
Extended survival of glioblastoma patients after chemoprotective HSC gene therapy.
Sci Transl Med. 2012; 4(133):133ra57 [PubMed] Free Access to Full Article Related Publications
Chemotherapy with alkylating agents for treating malignant disease results in myelosuppression that can significantly limit dose escalation and potential clinical efficacy. Gene therapy using mutant methylguanine methyltransferase (P140K) gene-modified hematopoietic stem and progenitor cells may circumvent this problem by abrogating the toxic effects of chemotherapy on hematopoietic cells. However, this approach has not been evaluated clinically. Here, we show efficient polyclonal engraftment of autologous P140K-modified hematopoietic stem and progenitor cells in three patients with glioblastoma. Increases in P140K-modified cells after transplant indicate selection of gene-modified hematopoietic repopulating cells. Longitudinal retroviral integration site (RIS) analysis identified more than 12,000 unique RISs in the three glioblastoma patients, with multiple clones present in the peripheral blood of each patient throughout multiple chemotherapy cycles. To assess safety, we monitored RIS distribution over the course of chemotherapy treatments. Two patients exhibited emergence of prominent clones harboring RISs associated with the intronic coding region of PRDM16 (PR domain-containing 16) or the 3' untranslated region of HMGA2 (high-mobility group A2) genes with no adverse clinical outcomes. All three patients surpassed the median survival for glioblastoma patients with poor prognosis, with one patient alive and progression-free more than 2 years after diagnosis. Thus, transplanted P140K-expressing hematopoietic stem and progenitor cells are chemoprotective, potentially maximizing the drug dose that can be administered.

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