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1.
Noncoding RNA ; 6(3)2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32630183

RESUMO

Nuclear paraspeckle assembly transcript 1 (NEAT1) is a long non-coding RNA (lncRNA) reported to be frequently deregulated in various types of cancers and neurodegenerative processes. NEAT1 is an indispensable structural component of paraspeckles (PSs), which are dynamic and membraneless nuclear bodies that affect different cellular functions, including stress response. Furthermore, increasing evidence supports the crucial role of NEAT1 and essential structural proteins of PSs (PSPs) in the regulation of the DNA damage repair (DDR) system. This review aims to provide an overview of the current knowledge on the involvement of NEAT1 and PSPs in DDR, which might strengthen the rationale underlying future NEAT1-based therapeutic options in tumor and neurodegenerative diseases.

2.
Genes (Basel) ; 9(2)2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29389884

RESUMO

Multiple myeloma (MM) is an incurable disease caused by the malignant proliferation of bone marrow plasma cells, whose pathogenesis remains largely unknown. Although a large fraction of the genome is actively transcribed, most of the transcripts do not serve as templates for proteins and are referred to as non-coding RNAs (ncRNAs), broadly divided into short and long transcripts on the basis of a 200-nucleotide threshold. Short ncRNAs, especially microRNAs, have crucial roles in virtually all types of cancer, including MM, and have gained importance in cancer diagnosis and prognosis, predicting the response to therapy and, notably, as innovative therapeutic targets. Long ncRNAs (lncRNAs) are a very heterogeneous group, involved in many physiological cellular and genomic processes as well as in carcinogenesis, cancer metastasis, and invasion. LncRNAs are aberrantly expressed in various types of cancers, including hematological malignancies, showing either oncogenic or tumor suppressive functions. However, the mechanisms of the related disease-causing events are not yet revealed in most cases. Besides emerging as key players in cancer initiation and progression, lncRNAs own many interesting features as biomarkers with diagnostic and prognostic importance and, possibly, for their utility in therapeutic terms as druggable molecules. This review focuses on the role of lncRNAs in the pathogenesis of MM and summarizes the recent literature.

3.
Oncotarget ; 8(36): 60605-60623, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28947998

RESUMO

B-cell malignancies constitute a large part of hematological neoplasias. They represent a heterogeneous group of diseases, including Hodgkin's lymphoma, most non-Hodgkin's lymphomas (NHL), some leukemias and myelomas. B-cell malignancies reflect defined stages of normal B-cell differentiation and this represents the major basis for their classification. Long non-coding RNAs (lncRNAs) are non-protein-coding transcripts longer than 200 nucleotides, for which many recent studies have demonstrated a function in regulating gene expression, cell biology and carcinogenesis. Deregulated expression levels of lncRNAs have been observed in various types of cancers including hematological malignancies. The involvement of lncRNAs in cancer initiation and progression and their attractive features both as biomarker and for therapeutic research are becoming increasingly evident. In this review, we summarize the recent literature to highlight the status of the knowledge of lncRNAs role in normal B-cell development and in the pathogenesis of B-cell tumors.

4.
Oncotarget ; 7(31): 50666-50681, 2016 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-27177333

RESUMO

Long non-coding RNAs (lncRNAs) are defined as ncRNAs of more than 200 nt in length. They are involved in a large spectrum of biological processes, such as maintenance of genome integrity, genomic imprinting, cell differentiation, and development by means of mechanisms that remain to be fully elucidated. Besides their role in normal cellular physiology, accumulating evidence has linked lncRNA expression and functions to cancer development and progression. In this review, we summarize and discuss what is known about their expression and roles in hematopoiesis with a particular focus on their cell-type specificity, functional interactions, and involvement in the pathobiology of hematological malignancies.


Assuntos
Neoplasias Hematológicas/genética , Hematopoese/genética , RNA Longo não Codificante/genética , Animais , Biomarcadores Tumorais/genética , Diferenciação Celular , Humanos , Camundongos , Prognóstico
5.
Genes Chromosomes Cancer ; 53(2): 154-67, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24327544

RESUMO

We explored the molecular mechanisms involved in the establishement of CMA-03/06, an IL-6-independent variant of the multiple myeloma cell line CMA-03 previously generated in our Institution. CMA-03/06 cells grow in the absence of IL-6 with a doubling time comparable with that of CMA-03 cells; neither the addition of IL6 (IL-6) to the culture medium nor co-culture with multipotent mesenchymal stromal cells increases the proliferation rate, although they maintain the responsiveness to IL-6 stimulation as demonstrated by STAT1, STAT3, and STAT5 induction. IL-6 independence of CMA-03/06 cells is not apparently due to the development of an autocrine IL-6 loop, nor to the observed moderate constitutive activation of STAT5 and STAT3, since STAT3 silencing does not affect cell viability or proliferation. When compared to the parental cell line, CMA-03/06 cells showed an activated pattern of the NF-κB pathway. This finding is supported by gene expression profiling (GEP) analysis identifying an appreciable fraction of modulated genes (28/308) in the CMA-03/06 subclone reported to be involved in this pathway. Furthermore, although more resistant to apoptotic stimuli compared to the parental cell line, CMA-03/06 cells display a higher sensibility to NF-κB inhibition induced by bortezomib. Finally, GEP analysis suggests an involvement of a number of cytokines, which might contribute to IL-6 independence of CMA-03/06 by stimulating growth and antiapoptotic processes. In conclusion, the parental cell-line CMA-03 and its variant CMA-03/06 represent a suitable model to further investigate molecular mechanisms involved in the IL-6-independent growth of myeloma cells.


Assuntos
Linhagem Celular Tumoral/metabolismo , Interleucina-6/metabolismo , Mieloma Múltiplo/metabolismo , Apoptose , Ácidos Borônicos/farmacologia , Bortezomib , Linhagem Celular Tumoral/patologia , Humanos , Interleucina-6/genética , Interleucina-6/farmacologia , Sistema de Sinalização das MAP Quinases , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Pirazinas/farmacologia , Transdução de Sinais , Transcriptoma
6.
Leuk Lymphoma ; 55(8): 1768-73, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24144314

RESUMO

Toll-like receptors (TLRs) represent major agents of innate immunity and initiators of adaptive immunity. TLR4 and TLR9 gene expression was related to the occurrence of infections, autoimmunity and disease progression in 95 patients with B-chronic lymphocytic leukemia (B-CLL), grouped according to stage, therapy and known prognostic markers, and followed prospectively (median 33.6 months, range 25-50). A retrospective analysis (median 6.8 years, range 6-26) was also performed. TLR4 gene expression was decreased and TLR9 increased in patients versus controls, the former being more pronounced in advanced and multi-treated disease, and in patients with unmutated immunoglobulin heavy chain variable (IgVH) region and unfavorable cytogenetics. Patients with reduced TLR4 had an increased risk of disease progression and development of autoimmune complications. No relationship was found between reduced TLR4 expression and infectious episodes, which were observed in advanced stages and treated patients. These findings suggest that impaired innate immunity identifies patients with B-CLL with a poor prognosis and reduced ability to silence autoreactive phenomena.


Assuntos
Expressão Gênica , Leucemia Linfocítica Crônica de Células B/genética , Receptor 4 Toll-Like/genética , Receptor Toll-Like 9/genética , Idoso , Idoso de 80 Anos ou mais , Autoimunidade , Biomarcadores/metabolismo , Progressão da Doença , Feminino , Humanos , Infecções/etiologia , Leucemia Linfocítica Crônica de Células B/complicações , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/terapia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Receptor 4 Toll-Like/metabolismo , Receptor Toll-Like 9/metabolismo , Resultado do Tratamento
7.
Eur J Haematol ; 85(2): 120-9, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20408870

RESUMO

OBJECTIVES: To describe the clinical and biological features of a series of immunophenotypic variant of B-CLL (v-CLL) characterised by intermediate RMH score, in the absence of t(11;14)(q13;q32) in FISH analysis in comparison with a series of typical CLL. METHODS: We studied the clinical and biological features of 63 cases of v-CLL and 130 cases of CLL. RESULTS: We observed significant differences in terms of age <70 yr (P < 0.001), lymphocytosis <20 x 10(9)/L (P < 0.001), lymphocyte doubling time

Assuntos
Leucemia Linfocítica Crônica de Células B/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Perfilação da Expressão Gênica , Rearranjo Gênico , Humanos , Cadeias Pesadas de Imunoglobulinas , Imunofenotipagem , Hibridização in Situ Fluorescente , Leucemia Linfocítica Crônica de Células B/classificação , Leucemia Linfocítica Crônica de Células B/diagnóstico , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Adulto Jovem
8.
Hematol Oncol ; 27(1): 23-30, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18759374

RESUMO

The protein kinase C (PKC) pathway has been shown to play a role in the regulation of cell proliferation in several haematological malignancies, including multiple myeloma (MM). Recent data have shown that a PKC inhibitor, enzastaurin, has antiproliferative and proapoptotic activity in a large panel of human myeloma cell lines (HMCLs). In order to further characterise the effect of enzastaurin in MM, we performed gene expression profiling of enzastaurin-treated KMS-26 cell line. We identified 62 upregulated and 32 downregulated genes that are mainly involved in cellular adhesion (CXCL12, CXCR4), apoptosis (CTSB, TRAF5, BCL2L1), cell proliferation (IGF1, GADD45A, BCMA (B-cell maturation antigen), CDC20), transcription regulation (MYC, MX11, IRF4), immune and defence responses. Subsequent validation by Western blotting of selected genes in four enzastaurin-treated HMCLs was consistent with our microarray analysis. Our data indicate that enzastaurin may affect important processes involved in the proliferation and survival of malignant plasma cells as well as in their interactions with the bone marrow microenvironment and provide a preclinical rationale for the potential role of this drug in the treatment of MM.


Assuntos
Regulação para Baixo/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes myc , Indóis/uso terapêutico , Fatores Reguladores de Interferon/genética , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Proteína Quinase C/antagonistas & inibidores , Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Mieloma Múltiplo/patologia , Proteína Quinase C beta
9.
Leuk Lymphoma ; 49(7): 1374-83, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18452078

RESUMO

Deregulation of the protein kinase C (PKC) signalling pathway has been implicated in tumor progression. Here we investigated the PKC inhibitor enzastaurin for its activity against multiple myeloma (MM) cells. Enzastaurin suppresses cell proliferation in a large panel of human myeloma cell lines (HMCLs), with IC50 values ranging from 1.3 to 12.5 microM and induces apoptosis, which is prevented by the ZVAD-fmk broad caspase inhibitor. These results are consistent with decreased phosphorylation of AKT and GSK3-beta, a downstream target of the AKT pathway and a pharmacodynamic marker for enzastaurin. Furthermore, enzastaurin cytotoxicity is retained when HMCLs were cocultured with multipotent mesenchymal stromal cells. Enzastaurin has additive or synergistic cytotoxic effects with bortezomib or thalidomide. Considering the strong anti-myeloma activity of enzastaurin in vitro and in animal models and its safe toxicity profile, phase II studies in MM patients of enzastaurin alone or in combination with other drugs are warranted.


Assuntos
Indóis/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Indóis/uso terapêutico , Concentração Inibidora 50 , Mieloma Múltiplo/patologia , Proteína Quinase C/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células Estromais/citologia
10.
Hematol Oncol ; 25(1): 6-10, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17036375

RESUMO

Ras gene mutations are a recurrent genetic lesion in multiple myeloma (MM). Here, we report a mutation analysis of N- and K-Ras genes in purified plasma cell populations from a panel of 81 newly diagnosed MM patients stratified according to the most frequent genetic and molecular features associated with the neoplasia. Ras gene mutations, mostly involving the N-Ras gene, were detected in 20% of the patients. Ras mutations did not correlate with the presence of chromosome 13q deletion, trisomy of chromosome 11, 1q amplification or hyperdiploidy. In addition, despite an appreciable association with tumours overexpressing Cyclin D1, Ras mutations did not correlate at significant levels with any of the proposed groups in the TC classification, based on the presence of the major IgH chromosomal translocations and expression of Cyclin D genes. Finally, transcription analyses revealed the presence of differentially expressed transcripts in human multiple myeloma cell lines carrying the Ras gene mutations but not in primary tumours. Overall, these data suggest that Ras gene mutations are not likely to represent a master lesion in MM but its relevance needs to be considered in the context of other genetic abnormalities.


Assuntos
Genes ras/genética , Mieloma Múltiplo/genética , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Aberrações Cromossômicas , Ciclina D , Ciclinas/genética , Feminino , Perfilação da Expressão Gênica , Heterogeneidade Genética , Humanos , Masculino , Pessoa de Meia-Idade , Ploidias , Células Tumorais Cultivadas
11.
Haematologica ; 90(11): 1541-8, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16266902

RESUMO

BACKGROUND AND OBJECTIVES: Established human myeloma cell lines (HMCL) have significantly contributed to the investigation of the biological aspects of multiple myeloma. Our study reports the molecular and biological characterization of three novel interleukin-6 (IL-6)-dependent HMCL (CMA-01, CMA-02, CMA-03) established from the malignant plasma cells of myeloma patients with extramedullary disease. DESIGN AND METHODS: The immunophenotype, cell growth characteristics, IL-6 pathway, chromosomal alterations and gene expression profiles of the three HMCL were investigated. RESULTS: The plasma cell origin of the three Epstein-Barr virus-negative HMCL was confirmed by immunophenotypic analysis. Cytogenetic and fluorescence in situ hybridization analyses revealed the presence of complex karyotypes with many numerical and structural chromosomal abnormalities. All three HMCL are positive for the t(8;14); CMA-01 and CMA-02 showed t(11;14) and t(14;16) translocations, respectively. The three HMCL grow slowly at a relatively low saturation density and depend on exogenous IL-6 for their survival and proliferation. The comparison of the gene expression profiles of the three HMCL versus those of the purified tumor plasma cells from which the cell lines were derived identified a set of differentially expressed genes mainly involved in the cell proliferation pathway. INTERPRETATION AND CONCLUSIONS: Extensively characterized large HMCL panels that reflect the heterogeneity of the disease may improve our understanding of the pathogenetic events and clinical progression of multiple myeloma.


Assuntos
Regulação Neoplásica da Expressão Gênica/fisiologia , Interleucina-6/fisiologia , Mieloma Múltiplo/metabolismo , Idoso , Proliferação de Células , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Interleucina-6/genética , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Transdução de Sinais/fisiologia , Células Tumorais Cultivadas
12.
Oncogene ; 24(15): 2461-73, 2005 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-15735737

RESUMO

Multiple myeloma (MM) is the most common form of plasma cell dyscrasia, characterized by a marked heterogeneity of genetic lesions and clinical course. It may develop from a premalignant condition (monoclonal gammopathy of undetermined significance, MGUS) or progress from intramedullary to extramedullary forms (plasma cell leukemia, PCL). To provide insights into the molecular characterization of plasma cell dyscrasias and to investigate the contribution of specific genetic lesions to the biological and clinical heterogeneity of MM, we analysed the gene expression profiles of plasma cells isolated from seven MGUS, 39 MM and six PCL patients by means of DNA microarrays. MMs resulted highly heterogeneous at transcriptional level, whereas the differential expression of genes mainly involved in DNA metabolism and proliferation distinguished MGUS from PCLs and the majority of MM cases. The clustering of MM patients was mainly driven by the presence of the most recurrent translocations involving the immunoglobulin heavy-chain locus. Distinct gene expression patterns have been found to be associated with different lesions: the overexpression of CCND2 and genes involved in cell adhesion pathways was observed in cases with deregulated MAF and MAFB, whereas genes upregulated in cases with the t(4;14) showed apoptosis-related functions. The peculiar finding in patients with the t(11;14) was the downregulation of the alpha-subunit of the IL-6 receptor. In addition, we identified a set of cancer germline antigens specifically expressed in a subgroup of MM patients characterized by an aggressive clinical evolution, a finding that could have implications for patient classification and immunotherapy.


Assuntos
Perfilação da Expressão Gênica , Predisposição Genética para Doença , Leucemia Plasmocitária/genética , Leucemia Plasmocitária/fisiopatologia , Mieloma Múltiplo/genética , Mieloma Múltiplo/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Ciclina D2 , Ciclinas/biossíntese , DNA de Neoplasias/análise , Regulação para Baixo , Feminino , Humanos , Cadeias Pesadas de Imunoglobulinas , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptores de Interleucina-6/biossíntese , Translocação Genética , Regulação para Cima
13.
Genes Chromosomes Cancer ; 42(2): 117-27, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15543617

RESUMO

Chromosomal translocations involving the immunoglobulin heavy chain (IGH) locus and various partner loci frequently are associated with multiple myeloma (MM). We investigated the expression profiles of the FGFR3/MMSET, CCND1, CCND3, MAF, and MAFB genes, which are involved in t(4;14)(p16.3;q32), t(11;14)(q13;q32), t(6;14)(p21;q32), t(14;16)(q32;q23), and t(14;20)(q32;q12), respectively, in purified plasma cell populations from 39 MMs and six plasma cell leukemias (PCL) by DNA microarray analysis and compared the results with the presence of translocations as assessed by dual-color FISH or RT-PCR. A t(4;14) was found in 6 MMs, t(11;14) in 9 MMs and 1 PCL, t(6;14) in 1 MM, t(14;16) in 2 MMs and 1 PCL, and t(14;20) in 1 PCL. In all cases, the translocations were associated with the spiked expression of target genes. Furthermore, gene expression profiling enabled the identification of putative translocations causing dysregulation of CCND1 (1 MM and 1 PCL) and MAFB (1 MM and 1 PCL) without any apparent involvement of immunoglobulin loci. Notably, all of the translocations were mutually exclusive. Markedly increased MMSET expression was found in 1 MM showing associated FGFR3 and MMSET signals on an unidentified chromosome. Our data suggest the importance of using combined molecular cytogenetic and gene expression approaches to detect genetic aberrations in MM.


Assuntos
Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/fisiologia , Hibridização in Situ Fluorescente/métodos , Análise em Microsséries/métodos , Mieloma Múltiplo/genética , Oncogenes/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas de Transporte/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 20/genética , Cromossomos Humanos Par 4/genética , Cromossomos Humanos Par 6/genética , Ciclina D1/genética , Ciclina D3 , Ciclinas/genética , Proteínas de Ligação a DNA/genética , Feminino , Histona-Lisina N-Metiltransferase , Humanos , Fatores Ativadores de Macrófagos/genética , Fator de Transcrição MafB , Masculino , Pessoa de Meia-Idade , Proteínas Oncogênicas/genética , Proteínas de Fusão Oncogênica , Proteínas Tirosina Quinases/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos , Receptores de Fatores de Crescimento de Fibroblastos/genética , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Translocação Genética/genética
14.
Genes Chromosomes Cancer ; 37(3): 261-9, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12759924

RESUMO

Chromosomal rearrangements of the MYC locus, which often involve the IG loci, are recurrent events in multiple myeloma (MM) and plasma cell leukemia (PCL). We used dual-color fluorescence in situ hybridization (FISH) to characterize the breakpoint locations of chromosomal translocations/rearrangements involving the MYC locus at 8q24 found in a panel of 14 MM cell lines and 70 primary tumors (66 MM and 4 PCL). MYC locus alterations were observed in 21 cases: MYC/IG (mainly IGH@) fusions in 11 cell lines and three patients (2 MM and 1 PCL), and extra signals and/or abnormal MYC localizations in seven patients (5 MM and 2 PCL). Fourteen of these cases were investigated by FISH analyses by use of a panel of BAC clones covering about 6 Mb encompassing the MYC locus. The breakpoints were localized in a region 100-250 kb centromeric to MYC in four cases, a region 500-800 kb telomeric to the gene in four cases, and regions > or = 2 Mb centromeric or telomeric to MYC in five cases. Two different breakpoints were detected in the KMS-18 cell line, whereas the insertion of a MYC allele was found in a complex t(16;22) chromosomal translocation in the RPMI8226 cell line. Our data document a relatively high dispersion of 8q24 breakpoints in MM.


Assuntos
Quebra Cromossômica/genética , Genes myc/genética , Heterogeneidade Genética , Marcadores Genéticos/genética , Mieloma Múltiplo/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Transformada , Cromossomos Humanos Par 8/genética , Feminino , Rearranjo Gênico/genética , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Proteínas de Fusão Oncogênica/genética , Translocação Genética/genética , Células Tumorais Cultivadas
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