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MicroRNA expression in Sézary syndrome: Identification, function and diagnostic potential.

ABSTRACT: MicroRNAs are commonly aberrantly expressed in many cancers. Very little is known of their role in T-cell lymphoma, however. We therefore elucidated the complete miRNome of purified T-cells cells from 21 patients diagnosed with Sézary syndrome (SzS), a rare aggressive primary cutaneous T-cell (CD4+) lymphoma. Unsupervised cluster analysis of microarray data revealed that the microRNA expression profile was distinct from CD4+ T-cell controls and B-cell lymphomas. The majority (104/114) of SzS-associated microRNAs (P < 0.05) were down-regulated and their expression pattern was largely consistent with previously reported genomic copy number abnormalities and were found to be highly enriched (P < 0.0001) for aberrantly expressed target genes. Levels of miR-223 distinguished SzS samples (n = 32) from healthy controls (n = 19) and patients with mycosis fungoides (n = 11) in >90% of samples. Furthermore, we demonstrate that the down-regulation of intronically encoded miR-342 plays a role in the pathogenesis of SzS by inhibiting apoptosis and describe a novel mechanism of regulation for this microRNA via binding of miR-199a* to its host gene. We also provide the first in vivo evidence for down-regulation of the miR-17-92 cluster in malignancy and demonstrate that ectopic miR-17-5p expression increases apoptosis and decreases cell proliferation in SzS cells.

ORGANISM(S): Mus musculus Rattus norvegicus Gallus gallus Homo sapiens

PROVIDER: GSE21697 | GEO | 2010/05/12

SECONDARY ACCESSION(S): PRJNA125867

REPOSITORIES: GEO

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Similar Datasets

MicroRNA expression in Sézary syndrome: Identification, function and diagnostic potential.

Project description:MicroRNAs are commonly aberrantly expressed in many cancers. Very little is known of their role in T-cell lymphoma, however. We therefore elucidated the complete miRNome of purified T-cells cells from 21 patients diagnosed with Sézary syndrome (SzS), a rare aggressive primary cutaneous T-cell (CD4+) lymphoma. Unsupervised cluster analysis of microarray data revealed that the microRNA expression profile was distinct from CD4+ T-cell controls and B-cell lymphomas. The majority (104/114) of SzS-associated microRNAs (P < 0.05) were down-regulated and their expression pattern was largely consistent with previously reported genomic copy number abnormalities and were found to be highly enriched (P < 0.0001) for aberrantly expressed target genes. Levels of miR-223 distinguished SzS samples (n = 32) from healthy controls (n = 19) and patients with mycosis fungoides (n = 11) in >90% of samples. Furthermore, we demonstrate that the down-regulation of intronically encoded miR-342 plays a role in the pathogenesis of SzS by inhibiting apoptosis and describe a novel mechanism of regulation for this microRNA via binding of miR-199a* to its host gene. We also provide the first in vivo evidence for down-regulation of the miR-17-92 cluster in malignancy and demonstrate that ectopic miR-17-5p expression increases apoptosis and decreases cell proliferation in SzS cells. CD4+ cells were purified from peripheral blood of 21 Sz patients and compared with 6 healthy controls.

2010-05-12 | E-GEOD-21697 | biostudies-arrayexpress

The transcription factor TAL1 and the miR-17-92 cluster establish a regulatory loop

Project description:A network of gene regulatory factors such as transcription factors and microRNAs establish and maintain the gene expression pattern during hematopoiesis. In this network transcription factors regulate each other and are involved in regulatory loops with microRNAs.The microRNA cluster miR-17-92 is located within the MIR17HG gene and encodes for six mature microRNAs. It is important for hematopoietic differentiation and plays a central role in malignant disease. However, the transcription factors downstream of miR-17-92 are largely elusive and the transcriptional regulation of miR-17-92 is not fully understood. Here we show that miR-17-92 forms a regulatory loop with the transcription factor TAL1. The miR-17-92 cluster inhibits expression of TAL1 and indirectly leads to decreased stability of the TAL1 transcriptional complex. We found that TAL1 and its heterodimerization partner E47 regulate miR-17-92 transcriptionally. Furthermore, miR-17-92 negatively influences erythroid differentiation, a process that depends on gene activation by the TAL1 complex. Our data give example of how transcription factor activity is fine-tuned during normal hematopoiesis. We postulate that disturbance of the regulatory loop between TAL1 and the miR-17-92 cluster could be an important step in cancer development and progression.

2021-09-09 | PXD018052 | Pride

Comparative genomic hybridization of 20 patients with Sézary syndrome

Project description:The transcription factor E2A is essential for lymphocyte development. In this study, we describe a recurrent E2A gene deletion in at least 70% of patients with Sézary syndrome (SS), a subtype of T cell lymphoma. Loss of E2A results in enhanced proliferation and cell cycle progression via derepression of the proto-oncogene MYC and the cell cycle regulator CDK6. Furthermore, by examining the gene expression profile of SS cells following restoration of E2A expression, we identify a number of E2A-regulated genes that interfere with oncogenic signaling pathways including the Ras pathway. Several of these genes are down-regulated or lost in primary SS tumor cells. These data demonstrate a tumor suppressor function of E2A in human lymphoid cells and could help to develop new treatment strategies for human lymphomas with altered E2A activity.

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Comparative gene expression profiling of cutaneous B cell lymphomas

Project description:The oncogenic microRNA 17-92 cluster is involved in the lymphomagenesis of nodal and systemic B cell lymphomas, but has not been studied so far in primary cutaneous B cell lymphomas. We performed the quantitative analysis of miR-17-92 cluster and its paralogs miR-106a-363 and miR-106b-25 in 22 primary cutaneous diffuse large B-cell lymphomas-leg type (PCLBCL-LT) and 22 primary cutaneous follicle center lymphomas (PCFCL). Mir-20a and miR-106a were overexpressed in PCLBCL-LT compared to PCFCL. Multivariate Cox analysis showed that higher miR-20a and miR-20b were associated with poorer disease-free survival and poorer overall survival, independently of histological type. Gene expression profiling showed underexpression of 8 candidate target genes of miR-20a, miR-20b and miR-106a in PCLBCL-LT compared to PCFCL. Among the candidate target genes, PTEN, NCOA3 and CAPRIN2 were confirmed to be underexpressed in PCLBCL-LT using quantitative RT-PCR of laser-microdissected tumor cells. In multivariate Cox analysis, lower PTEN mRNA expression level was associated with poorer disease-free survival, independently of the histological type. Altogether, this molecular and bioinformatics study of patients’ skin biopsy samples showed that the oncogenic miR-17-92 cluster is involved in cutaneous B cell lymphoma progression, and that the down-regulation of its target gene PTEN is associated with poorer disease-free survival.

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Project description:The synergism between c-MYC and miR-17-19b, a truncated version of the miR-17-92 cluster, is well documented during tumor initiation. However, little is known about miR-17-19b function in established cancers. Here we investigate the role of miR-17-19b in c-MYC-driven lymphomas by integrating SILAC-based quantitative proteomics, transcriptomics and 3’ UTR analysis upon miR-17-19b overexpression. We identify over one hundred novel miR-17-19b targets, of which 40% are co-regulated by c-MYC. Down-regulation of a new miR-17/20 target Chek2 increases the recruitment of HuR to c-MYC transcripts, resulting in the inhibition of c-MYC translation and thus interfering with in vivo tumor growth. Hence, in established lymphomas, miR-17-19b fine-tunes c-MYC activity through a tight control of its function and expression, ultimately ensuring cancer cell homeostasis. Our data highlight the plasticity of miRNA function, reflecting changes in the mRNA landscape and 3’ UTR shortening at different stages of tumorigenesis.

2015-11-06 | PXD002810 | Pride

Affymetrix SNP array data for Sézary Syndrome (SS) samples

Project description:This study used tumour and paired normal samples from 28 Sézary Syndrome (SS) patients to define recurrent regions of chromosomal aberrations. Our data identified recurrent losses of 17p13.2-p11.2 and 10p12.1-q26.3 occurring in 71 and 68% of cases respectively; common gains were detected for 17p11.2-q25.3 (64%) and chromosome 8/8q (50%). Moreover, we identified novel genomic lesions recurring in more than 30% of tumours: loss of 9q13-q21.33 and gain of 10p15.3-10p12.2. In the Sézary Syndrome cases analysed, we could find several small and few large Uniparental Disomies involving interstitial or telomeric regions of LOH occurring mainly for chromosome 10 and to a lesser extent for chromosome 9 and 17. In the attempt to correlate Copy Number data and clinical parameters we find a relationship between complex pattern of chromosomal aberrations, involving at least three recurrent Copy Number alterations, and shorter survival. Integrating mapping and transcriptional data we were able to identify a total of 113 deregulated transcripts in aberrant chromosomal regions that included cancer related genes such as members of the NF-kB pathway (BAG4, BTRC, NKIRAS2, PSMD3, TRAF2) that might explain its constitutive activation in CTCL. Matching this list of genes with those discriminating patients with different survival times we identify several common candidates that might exert critical roles in Sézary Syndrome, like BUB3 and PIP5K1B.

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Affymetrix Gene Expression array data for Sézary Syndrome (SS) samples

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mRNA expression data from primary untreated neuroblastoma tumour samples

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2010-12-01 | GSE21713 | GEO

miRNA expression in E18.5 murine total lung tissue

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2019-11-10 | GSE123671 | GEO

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