De novo double-hit B-cell precursor leukemia/lymphoma - an unusual presentation as peritoneal lymphomatosis

Peritoneal lymphomatosis (PL) is a rare presentation of extranodal precursor leukemia/lymphoma. The presentation is often non-specific, leading to delayed diagnosis and treatment. In this case, though the preliminary diagnosis was established on ascitic fluid cytology, the disease progressed rapidly, leading to demise before initiating chemotherapy. Immunophenotyping and molecular studies, performed later, established a diagnosis of de novo B-cell precursor leukemia/lymphoma with MYC, BCL2 rearrangements (Double-hit lymphoma). MYC, BCL2 rearrangements are rarely reported in precursor B-lymphoma/leukemia which carry dismal prognosis. In this report, we illustrate autopsy findings of PL in an elderly gentleman who presented with ascites for evaluation.

Estudos funcionais e biológicos associados à interação de DUSP3 com a proteína HNRNPC1/C2 / Functional and biological studies associated to DUSP3 and HNRNPC1/C2 protein inte ractions

A regulação da fosforilação/desfosforilação das proteínas é o eixo central de muitas cascatas de sinalização. A fosfatase DUSP3, constituída apenas por um único domínio catalítico, desempenha papéis fundamentais na proliferação e senescência celular. Nas células HeLa, submetidas ao estresse genotóxico, o DUSP3 interage fisicamente com as proteínas HNRNPC, mas o efeito dessa função molecular ainda é desconhecido. Aqui demostramos que a ausência de DUPS3 mantem a proteína HNRNPC1/C2 num estado hiperfosforilado. Para entender melhor o envolvimento da interação DUSP3-HNRNPC nas funções biológicas da HNRNPC1/C2, foram estudadas células de fibroblasto deficientes de DUSP3. Foi analisado o efeito da deficiência de DUSP3 na biogênese dos ribossomos através do ensaio de perfil de polirribossomos e quantificação dos rRNAs com RT-qPCR. Os resultados mostraram que a deficiência de DUSP3 não afeta a maturação das subunidades ribossômicas, mas teria um impacto na transcrição dos pré-rRNAs e no acumulo das espécies 47S/45S. A expressado de genes contendo sequencias IRES foi analisado através do RT-qPCR e sua tradução ao longo do ciclo e em condições de estresse. Da expressão, não existe nenhuma diferença nos níveis de transcrição dos genes c-myc e xiap nas células normais e deficientes de DUSP3 em condições basais. Embora a síntese destas proteínas é maior nas células deficientes, mantendo um nível maior de tradução ao longo de todo o ciclo. Sob condições de estresse, esta duas proteínas sempre mantem uma maior expressão nas células Knockdown para DUSP3. Neste trabalho também foi estabelecido a presença de DUSP3 nos complexos da subunidade 40S, através do analise das frações obtidas do ensaio de polirribossomos e interação in vitro (Co-IP). A presença de DUSP3 nas subunidades 40S, os monossomas 80S e polissomos poderia ser através da interação direta com proteínas que possuem um domínio RRM e seria dependente dos complexos formados pelas proteínas e seus RNAs alvos. Aqui mostramos a interação in vitro de DUSP3 com a proteína PABP (com quatro domínios RRM), proteína que tem um papel importante na manutenção da taxa global de tradução, esta interação é enfraquecida na ausência de RNAs. A deficiência de DUSP3 também teria um impacto na interação das proteínas HNRNPC1/C2 e P53 in vitro. A ausência de DUSP3 diminui a interação HNRNPC-P53 através da hiperfosforilação da proteina HNRNPC1/C2. A perda desta interação, aumentaria os níveis da proteína P53 na célula deficiente de DUSP3 e poderia gerar parada no ciclo celular. Através de ensaios de imunofluorescência, se observo uma maior taxa de transcrição global na célula deficiente de DUSP3. Por fim, aqui demostramos que a interação direta de DUSP3 e HNRNPC1/C2 vai permitir a regulação das funções biológicas desta proteína, e a ausência de DUSP3 vai ter efeitos pleiotrópicos na homeostase da célula

inglêsProtein phosphorylation/dephosphorylation regulation is a central axis of many signaling cascades. DUSP3 phosphatase, consisting only of a single catalytic domain, plays key roles in cell proliferation and senescence. In HeLa cells subjected to genotoxic stress, DUSP3 physically interacts with HNRNPC proteins, but the effect of this molecular function is still unknown. Here we demonstrate that the absence of DUPS3 keeps the HNRNPC1/C2 proteins in a hyperphosphorylated state. To better understand the involvement of DUSP3- HNRNPC interaction on the biological functions of HNRNPC1/C2, DUSP3 deficient fibroblast cells were studied. The effect of DUSP3 deficiency on ribosome biogenesis was analyzed by polyribosome profile assay and RT-qPCR for rRNA quantification. The results showed that DUSP3 deficiency does not affect ribosomal subunit maturation, but would have an impact on transcription of pre-rRNAs and accumulation of 47S / 45S species. The expression of genes containing IRES sequences was analyzed by RT-qPCR and their translation throughout the cycle and under stress conditions. From expression, there is no difference in transcriptional levels of c-myc and xiap genes in normal and DUSP3 deficient cells under basal conditions. Although, the synthesis of these proteins is higher in deficient cells and these maintain a higher level of translation throughout the cell cycle. Under stress conditions, these two proteins always maintain higher expression in Knockdown cells for DUSP3. In this work, the presence of DUSP3 in the 40S ribosomal subunit complexes was also established by analyzing the fractions obtained from the polyribosome assay and in vitro interaction (CoIP). The presence of DUSP3 in the 40S subunits, 80S monosomes and polysomes could be through direct interaction with proteins that have an RRM domain and would be dependent on the complexes formed by the proteins and their target RNAs. Here we show the in vitro interaction of DUSP3 with PABP protein (with four RRM domains), a protein that plays an important role in maintaining the overall translation rate, this interaction is weakened in the absence of RNAs. DUSP3 deficiency would also have an impact on the interaction of HNRNPC1/C2 and P53 proteins in vitro. The absence of DUSP3 decreases HNRNPC-P53 interaction through hyperphosphorylation of the HNRNPC1/C2 proteins. Loss of this interaction would increase P53 protein levels in the DUSP3 deficient cell and could lead to cell cycle arrest. Through immunofluorescence assays, a higher overall transcription rate is observed in the DUSP3 deficient cell. Finally, we demonstrate that the direct interaction of DUSP3 and HNRNPC1/C2 will allow the regulation of the biological functions of this protein, and the absence of DUSP3 will have pleiotropic effects on cell homeostasis

Malignant transformation in a Breast Adenomyoepithelioma Caused by Amplification of c-MYC: A Common pathway to Cancer in a Rare Entity / 한국유방암학회지

Breast adenomyoepitheliomas are composed of a biphasic proliferation of myoepithelial cells around small epithelial-lined spaces. Due to the rarity of adenomyoepitheliomas, the molecular data describing them are limited. Adenomyoepitheliomas are considered to be benign or have low malignant potential, and be prone to local recurrence. Malignant transformation has been associated with homozygous deletion of CDKN2A or somatic mutations in TERT, but remains unexplained in many cases. Here, we describe a case of carcinomatous transformation of both epithelial and myoepithelial cells in an estrogen receptor-negative adenomyoepithelioma caused by amplification of MYC. Break-apart fluorescence in situ hybridization revealed an increase in the MYC gene copy number (3–4 copies/cell in 37%, > 4 copies/cell in 40%). Deregulation of MYC is responsible for uncontrolled proliferation and cellular immortalization in basal-like breast cancers. Our case demonstrates that genomic instability events associated with gene amplification may be involved in the carcinogenesis of malignant adenomyoepitheliomas.

Evolución de un linfoma no Hodgkin "triple expresor" en un paciente trasplantado renal con quimioterapia DA-R-EPOCH. Caso clínico / Triple expressor lymphoma in a kidney transplant patient

Patients transplanted from solid organs have an increased risk of cancer, especially lymphomas. Lymphomas correspond to 4 to 5% of malignant neoplasms in the general population and in solid organ transplant patients it reaches an incidence of 21%. The incidence of non-Hodgkin lymphomas is 10 times higher than in the non-transplanted population. We report the case of a 68-year-old man with a kidney transplant who 6 years after transplantation, developed a non-Hodgkin diffuse large cells B lymphoma with lymph node and pulmonary involvement, with markers of very poor prognosis (triple MYC expressor, BCL2 and BCL6). and its evolution with chemotherapy with DA R EPOCH.

Cutaneous Angiosarcoma of the Foot Accompanied by Multiple Myeloma: The First Case Report / 대한피부과학회지

Although the exact etiology of cutaneous angiosarcoma remains unclear, MYC gene amplification has been recently discovered as a new pathogenesis. MYC is a proto-oncogene, and aberration of MYC signaling in malignancies is associated with tumor metastasis, recurrence, and mortality. Moreover, upregulation of the miRNA polycistron, miR-17-92 cluster, were confirmed in both cutaneous angiosarcoma and multiple myeloma with MYC amplification. The correlation between MYC and miRNA expression is predictable as the coincident aberrant phenotype in two diseases. Moreover, the exploiting MYC dependency may be an attractive disease-specific strategy for the diagnosis and treatment of patients who are unaware of the causes of cutaneous angiosarcoma. Herein, a rare case of cutaneous angiosarcoma of the foot, which is also the first case of cutaneous angiosarcoma accompanied by multiple myeloma, has been described.

Linfoma primario de bazo difuso de células grandes B doble hit: un subtipo de mal pronóstico / Primary splenic diffuse large B-cell lymphoma double hit: A subtype of poor prognosis

Resumen El linfoma difuso de células grandes B (LDCGB) es el tipo de linfoma más frecuente, constituyendo un 35% de todos los casos de linfoma no Hodgkin (LNH). El linfoma no-Hodgkin primario de bazo (LNHPB) presenta una incidencia menor al 1% de todos los linfomas. Los linfomas doble hit están relacionados con el reordenamiento del gen MYC asociado a otra alteración molecular. Tienden a presentarse en varones de edad avanzada y se caracterizan principalmente por su comportamiento agresivo.

Abstract Diffuse Large-cell Lymphoma B (DLCLB) is the most common type of lymphoma, constituting 35% of all cases of Non-Hodgkin's Lymphoma (NHL). Primary Splenic Non-Hodgkin Lymphoma (PS-NHL) has an incidence of less than 1% of all lymphomas. The ''double hit'' lymphomas are related to the rearrangement of the MYC gene associated with another molecular alteration. They used to appear in older men and are mainly characterised by their aggressive behaviour.

Clinicopathological Features and Prognostic Factors of DLBCL / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To analyze the clinicopathological features and prognostic factors of patients with diffuse large B-cell lymphoma(DLBCL).</p><p><b>METHODS</b>Ninety-four cases of DLBCL followed up were selected in Fujian Tumor Hospital. The immunohistochemistry method was used to detect the protein expressions of BCL-2 BCL-6, MYC, CD10 and MUM-1, the gene abnormalities of MYC and BCL-2 were analyzed by fluorescence in situ hybridization, and the clinical pathological features and the related factors affecting prognosis in the patients with DLBCL were analyzed.</p><p><b>RESULTS</b>The protein positive rates of BCL-2, BCL-6, MYC, CD10 and MUM-1 in 94 patients were 75.53% (71/94), 58.51% (55/94), 52.13% (49/94), 15.96% (15/94) and 34.04% (32/94) respectively. The detection rate of MYC gene abnormality was 20.93% (9/43) and the detection rate of BCL-2 gene abnormality was 44% (22/50); 2 kinds of gene abnormalities were of multiple copies, and 2 cases (2.13%) were abnormal in MYC and BCL-2 genes simultaneously. The median survival time of 3 years in 94 patients was 21.79 months (2-36 months), and the overall survival rates of 1 and 3 years were 82.98% and 64.89% respectively. Single factor analysis revealed that the high ECOG score (≥ 2), high international prognostic index (IPI) classification, positive expression of BCL-6 protein, and MYC and BCL-2 gene simultaneously abnormal were the risk factors influencing the prognosis (all P<0.05). COX regression analysis showed that IPI classification, ECOG score and treatment methods were independent factors influencing the prognosis (all P<0.05).</p><p><b>CONCLUSION</b>IPI classification, ECOG score and treatment methods have greater impacts on the prognosis of patients with DLBCL. Chemotherapy combined with radiotherapy or surgical treatment can significantly improve the prognosis of patients.</p>

Expression Study and Clinical Correlations of MFC and CCAT2 in Breast Cancer Patients

Background: Colon cancer-associated transcript 2 [CCAT2] is a newly recognized IncRNA transcribed from the 8q24 genomic region. It functions as an oncogene in various types of cancers including breast cancer, in which it affects Wnt/p-catenin pathway. Previous studies have shown a putative interaction between this IncRNA and MYC proto-oncogene

Methods: In the current study, we evaluated the expression of CCAT2 in breast cancer tissues with regards to the expression of its target MYC. In addition, we assessed the relationship between CCAT2 and MYC expression levels in tumor tissues and the clinical prognostic characteristics of breast cancer patients

Results: MYC expression levels were significantly up-regulated in tumor tissues compared with adjacent non-cancerous tissues [ANCTs], while such analysis showed no statistically significant difference between these two tissue types in CCAT2 expression. Starkly increased CCAT2 gene expression levels were found in 12/48 [25%] of cancer tissue samples compared with their corresponding ANCTs. Furthermore, significant inverse correlations were found between CCAT2 expression and stage, as well as lymph node involvement. Besides, a significant inverse correlation was found between the relative MYC expression in tumor tissues compared with their corresponding ANCTs and disease stage

Conclusions: These results highlight the significance of MYC and CCAT2 expressions in the early stages of breast cancer development and suggest a potentially significant role for CCAT2 in a subset of breast cancer patients, which could be applied as a potential therapeutic target in these patients

Insertion of the LINE-1 element in the C-MYC gene and immunoreactivity of C-MYC, p53, p21 and p27 proteins in different morphological patterns of the canine TVT / Inserção do elemento LINE - 1 no gene C-MYC e imunorreatividade das proteinas C-MYC, p53, p21 e p27 nos diferentes padrões morfológicos do tumor TVT

The canine transmissible venereal tumor (TVT) affects the external genitalia of dogs by the natural transplant of viable tumor cells. Thus, this research aimed to diagnose and characterize TVT morphological patterns, identify the insertion of the LINE-1 element in C-MYC gene, by means of the polymerase chain reaction (PCR), and evaluate the immunohistochemical expression of C-MYC, p53, p21 and p27 proteins. The relationship between C-MYC and p53 proteins and their interference on the expression of p21 and p27 were also studied. For that, 20 samples of naturally occurring TVT were used, subjected to cytopathological, histopathological and immunohistochemical analysis, and to molecular diagnosis of neoplasia. The increased tissue expression and the correlation among C-MYC, p53, p21 and p27 proteins indicate reduction and/or loss of their functionality in the TVT microenvironment, with consequent apoptotic suppression, maintenance of cell growth and progression of neoplasia.(AU)

O tumor venéreo transmissível canino (TVT) afeta a genitália externa de cães pelo transplante natural de células tumorais viáveis. Assim, esta pesquisa teve como objetivo diagnosticar e caracterizar TVT em padrões morfológicos, identificar a inserção do elemento LINE-1 em gene C-MYC, por meio da reação em cadeia da polimerase (PCR), e avaliar a expressão imuno-histoquímica do C-MYC, p53, p21 e p27. A relação entre C-MYC e as proteínas p53 e a sua interferência na expressão de p21 e p27 foram também estudadas. Para isso, foram utilizadas 20 amostras de ocorrência natural de TVT, submetido a exame citopatológico, histopatológica e imuno-histoquímica e ao diagnóstico molecular de neoplasia. A expressão aumentada do tecido e a correlação entre a C-MYC e as proteínas p53, p21 e p27 indicam redução e/ou perda de funcionalidade na TVT em seu microambiente, com consequente supressão apoptótica, manutenção do crescimento celular e progressão da neoplasia.(AU)

Perfil de expressão de microRNAs regulados por C-MYC no linfoma de Burkitt / [Expression profile of C-MYC-regulated microRNAs in Burkitt's lymphoma]

O Linfoma de Burkitt (LB), subtipo de linfoma não Hodgkin B mais frequente na infância, é uma neoplasia hematológica altamente agressiva. A assinatura molecular é a translocação (8;14) ou suas variantes: t(2;8) e t(8;22). Ambas as translocações envolvem o proto-oncogene c-MYC que quando translocado é expresso constitutivamente, caracterizando a principal alteração conhecida no LB. Atualmente, tem sido demonstrado que c-MYC regula a expressão de vários miRNAs, dentre eles o cluster de miR-17-92 e a família miR-34, entreoutros. Neste contexto, o balanço entre c-MYC e miRNAs parece ser crítico para a patogênese do LB e necessita ser melhor elucidado. Nesse estudo avaliamos a expressão dos miRNAs regulados por c-MYC (cluster 17-92: miR-17, miR-19a/b, miR-20a, miR-92a e da família miR-34) em 57 amostras tumorais de LB pediátrico. Adicionalmente, avaliamos a correlação entre os níveis de miR-17, miR-19a/b, miR-20a e miR-92a e a expressão de um dos seus principais alvos, a proteína pró-apoptótica BIM. Foi observado que níveis elevados do miR-17 e miR-20a estavam associados com a ausência da expressão de BIM (p<0,001). Em sequência, observamos que o aumento do miR-17 estava fortemente correlacionado com uma sobrevida global (SG) inferior (p=0,007). A análise multivariada revelou também que miR-17 foi um preditor significativo de SG encurtada. A inibição do miR-17 em linhagem de LB resultou em aumento da proteína BIM, reforçando o papel deste miRNA na regulação deBIM...

Burkitt lymphoma (BL) is highly aggressive subtype of B-non-Hodgkin more frequent in childhood and associated with the translocation (8, 14) or its variations: t(2, 8) or t(8, 22). The proto-oncogene c-MYC is involved in all translocations and it is juxtaposed to Igs gene enhancers being expressed constitutively. It has been demonstrated that c-MYC regulates alarge number of miRNAs, including the cluster miR-17-92 and miR-34 family. Thus, the balance between Myc and miRNAs may be critical to the BL pathogenesis and needs furtherelucidation. In this study, we investigated miR-17, miR-19a, miR-19b, miR-20 and miR-92a expression levels in a series of 57 BL tumor samples. In addition, pro-apoptotic BIM proteinexpression was evaluated and then compared to miR-17, miR-19a, miR-19b, miR-20 and miR-92a levels, and patient outcomes. We found that upregulated expression of miR-17, andmiR-20a correlates with lack of pro-apoptotic BIM protein expression (p<0.001). Patients bearing tumors with upregulated miR-17 displayed decreased overall survival (OS) (p=0.007). Moreover, the multivariate analysis revealed that miR-17 was a significant predictor of shortened OS. Using hairpin inhibitor we showed that inhibition of miR-17 resulted inenhanced BIM expression in a BL cell line, suggesting the involvement of this miRNA in the regulation of BIM protein. Besides, low expression levels of miR-34a/b/c were observed in BL tumor samples. Next, we evaluated whether these miRNAs were suppressed by DNAmethylation. So, we analyzed the effect of demethylant agent 5-aza-2-deoxycytidine (decitabine) on miR-34 expression levels in BL cell lines. We observed an increase of miR-34b levels in BL41, Daudi and Raji cell lines in all decitabine concentrations. Then, we also detected that the treatment with higher concentration of decitabine resulted in the c-MYCmRNA reduction in Daudi and Raji (0.83 and 1.4 times, respectively)...

Avaliação de Características Clínico-Patológicas e Moleculares na Resposta à Quimioterapia no Câncer de Mama Localmente Avançado / [Evaluation of Clinical, Pathological and Molecular Characteristics in Response to Chemotherapy in Locally Advanced Breast Cancer]

A quimioterapia neoadjuvante refere-se à administração de quimioterápico antes do tratamento locorregional, e é um tratamento padrão em tumores de mama localmente avançados. O câncer de mama é uma patologia heterogênea, onde tumores apresentam comportamento biológico e diferentes respostas à quimioterapia neoadjuvante, mesmo com estadiamentos iguais. Com base na análise concomitante da expressão do receptor-2 do fator de crescimento epidérmico humano (HER-2/c-erbB-2), da proteína Ki67 e de receptores hormonais de estrógeno e progesterona, o câncer de mama é dividido subtipos moleculares, os quais são úteis para orientar as decisões de tratamento, porém apresentam ambiguidades. Neste contexto, propusemos que os genes MYC e KRAS podem ser candidatos a biomarcadores com valor preditivo e prognóstico, visto que as suas proteínas são alvo dos sinais proliferativos dirigidos pelaproteína HER-2 em células de câncer de mama e porque a proteína MYC pode ser regulada pelos receptores de estrogênio ou progesterona. Este estudo foi dividido em duas fases, uma retrospectiva e uma prospectiva. Os resultados retrospectivos da analise de 116 amostras tumorais geraram a primeira publicação científica que descreve o significado preditivo e prognóstico das alterações dos genes MYC e KRAS em pacientes com câncer de mama localmente avançado, tratados com quimioterapianeoadjuvante padrão com antraciclina e ciclofosfamida (AC). A avaliação conjunta da idade da paciente, do grau tumoral, do subtipo molecular e das alterações dos genes MYC e KRAS revelou que a amplificação do gene MYC é um fator preditivo de quimiossensibilidade ao tratamento AC, em pacientes de idade ≤ 40 anos, com tumores de grau 1, dos subtipos luminal B e HER-2. Enquanto que a mutaçãodo códon 12 do gene KRAS foi a única variável independente observada no modelo de regressão logísticapara avaliar fatores de risco para o grau tumoral e foi interpretada como um biomarcador de mau prognóstico...

Neoadjuvant chemotherapy refers to the administration of chemotherapy prior to locoregional treatment,being a standard procedure of locally advanced breast cancer. Breast cancer is a heterogeneous disease where tumors with the same histological types and stage have different responses to neoadjuvant chemotherapy. Based on simultaneous analysis of the expression of the receptor-2, the human epidermalgrowth factor (HER-2 / c-erbB-2), the Ki67 protein and hormone receptors for estrogen and progesterone, breast cancer is divided into molecular subtypes, which are useful to guide treatment decisions, however there are ambiguities. In this context, we propose that MYC and KRAS may bebiomarkers candidates for predictive and prognostic value, since their proteins are targets of proliferativesignals driven by HER-2 protein in breast cancer cells and also, because MYC protein can be regulatedby estrogen and/or progesterone receptors. This study was divided into two phases; a retrospective anda prospective phase. Retrospective analysis of 116 tumor samples generated the first article describingthe predictive and prognostic values on MYC and KRAS changes in patients with locally advanced breast cancer treated with standard neoadjuvant chemotherapy with anthracycline and cyclophosphamide (AC). The joint assessment of the patient's age, tumor grade, molecular subtype and changes on MYC and KRAS genes revealed that the amplification of MYC gene is a predictor of chemosensitivity toACtreatment, on patients age of ≤ 40 years with tumors grade 1, luminal subtypes B and HER-2+.Mutationon codon 12 of the KRAS gene was the only independent variable observed in the logistic regression model to assess risk factors being interpreted as a biomarker of poor prognosis. In the prospective phase, we evaluated the role of described biomarkers as predictors of response to neoadjuvant chemotherapy with AC follow...

Effect of BRD4 Inhibitor JQ1 on Proliferation Inhibition and Apotosis Induction in Jurkat Cells / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To investigate the effect and possible mechanism of bromo-domain inhibitors (JQ1) on proliferation inhibition and inducing apoptosis of acute T lymphocyte leukemia cell line (Jurkat) .</p><p><b>METHODS</b>Jurkat cell line was treated by JQ1 at different concentrations. MTT was used to detect the cell proliferation inhibition rate. The flow cytometry with AnnexinV-FITC/PI fluorescence staining was used to detect the changes of apoptosis rate, and real-time fluorescent quantitative PCR was used to detect c-Myc/Notch1 gene expression levels.</p><p><b>RESULTS</b>With the increasing of drug concentration and prolonging of time, the inhibitory rate of Jurkat cell growth was enhanced in time-dose dependent manner; Jurkat cells was treated by 0.8, 1.6, and 4 µ mol/LJQ1 for 48 h and 72 h, the cell apoptosis rate was enhanced with the increase of drug concentration and prolonging of time, and the difference was statistically different in comparison with the control group(P<0.05); PCR detection indicated that Notch1 and c-Myc mRNA expression was reduced in 48 h after JQ1 treatment, which was statistically different from the control group,(P<0.05) .</p><p><b>CONCLUSION</b>JQ1 can effectively inhibit the growth of Jurkat cell line, and potentially induce apoptosis through Notch1 and c-Myc gene. Hence JQ1 may be one of new methods used to treat T-ALL.</p>

Advances Research on C-MYC Proto-oncogene in Multiple Myeloma -Review / 中国实验血液学杂志

Multiple myeloma(MM) as one of the most common tumors of hmatologic system, is characterized by malignant proliferation of plasma cells, and the chemotherapy is the main therapeutic method. MM is an incurable disease because of drug-resistance of MM cells. Although the pathogenesis of MM remains unknown, the chromosome abnormalities exit in half of the patients, particularly the highly expressed gene C-MYC. Furthermore, plenty of clinical researches indicated a high expression level of C-MYC implied worse progression and/or poor prognosis of MM. Recently, the work exploiting the compounds targeting MYC has made substantial progress, even in the MM therapy. In this article, briefly the recent advances of the research on C-MYC proto-oncogene in multiple myeloma are reviewed.

Effect of Decitabine on DKK1 Gene Demethylation in Leukemia Cells / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To explore the effect of decitabine on Dickkopf-1 (DKK1) gene expression level and its downstream Wnt signaling pathway in acute myeloid leukemia (AML) cell line HL-60.</p><p><b>METHODS</b>Flow cytometry and DNA ladder analysis were performed to detect apoptosis in HL-60 cell treated with different concentration of decitabine. Methylation-specific polymerase chain reaction (MS-PCR) was used to examine the methylation status of DKK1 gene. The expressions of mRNA and protein were determined by qRT-PCR and Western blot, respectively.</p><p><b>RESULTS</b>Flow cytometric detection showed that after treating HL-60 cell line with decitabine of different concentrations for 48 h, the early apoptosis of HL-60 cells increased significantly as compared with control group (P < 0.05). DNA ladder analysis showed that the DNA ladder and demethylation of DKK1 gene appeared. RT-PCR and Western blot showed that the expressions of mRNA and protein increased. The protein expressions of β-catenin and C-MYC decreased.</p><p><b>CONCLUSION</b>The decitabine can promote the apoptosis of HL-60 cells throngh demethylation of DDK1 gene and inhibition of Wnt signalling pathway.</p>

Esophageal eosinophilia in pediatric patients with cerebral palsy / Eosinofilia esofágica em pacientes pediátricos com paralisia cerebral

ABSTRACT Objective: To describe the clinical picture, test results, and clinical evolution of patients with cerebral palsy associated with diagnosis of eosinophilic esophagitis, monitored at tertiary centre. Methods: Cross-sectional, retrospective and descriptive study that evaluated the medical records data of pediatric patients with diagnosis of cerebral palsy and eosinophilic esophagitis in a tertiary center of pediatric gastroenterology between August 2005 and August 2013. Results: Seven out of 131 patients with cerebral palsy had the diagnosis of eosinophilic esophagitis. The mean age at diagnosis of eosinophilic esophagitis was 52.3 months and the mean number of eosinophils in esophagus was 35 per high-power field. Symptoms more frequent were recurrent vomiting and disphagia. Endoscopic alterations found were mucosal thickening, vertical lines, mucosal opacificacion and white plaques. Conclusion: The frequency of eosinophilic esophagitis found was higher than in general pediatric population. The investigation of eosinophilic esophagitis should be done regularly in those patients, once this entity could overlap other gastrointestinal diseases. .

RESUMO Objetivo: Descrever quadro clínico, resultados dos exames e evolução clínica de pacientes com paralisia cerebral associada ao diagnóstico de esofagite eosinofílica, monitorados em um centro terciário. Métodos: Estudo transversal, retrospectivo e descritivo, que avaliou os prontuários médicos de pacientes pediátricos com diagnóstico de paralisia cerebral e esofagite eosinofílica, atendidos em um centro terciário de gastrenterologia pediátrica, entre agosto de 2005 e agosto de 2013. Resultados: Dos 131 pacientes com paralisia cerebral, 7 tiveram o diagnóstico de esofagite eosinofílica no período estudado. A idade média no momento do diagnóstico de esofagite eosinofílica foi 52,3 meses, e o número médio de eosinófilos no esôfago foi de 35 por campo de grande aumento. Os sintomas mais frequentes associados foram vômitos recorrentes e disfagia. As alterações endoscópicas encontradas foram espessamento da mucosa, linhas verticais, opacificação da mucosa e as placas esbranquiçadas. Conclusão: A frequência de esofagite eosinofílica encontrada foi maior que na população pediátrica em geral. A investigação de esofagite eosinofílica deve ser realizada regularmente nos pacientes com paralisia cerebral, pois pode haver uma sobreposição de sintomas de outras doenças gastrintestinais. .

miR-205 promotes proliferation and invasion of laryngeal squamous cell carcinoma by suppressing CDK2AP1 expression

BACKGROUND: The aberrant expression of microRNAs (miRNAs) has been found in various types of cancer. miR-205 was reported to be upregulated in laryngeal squamous cell carcinoma (LSCC) tissues, however, the mechanisms by which miR-205 functions as a regulator of LSCC are largely unknown. RESULTS: In this study, Real-time qPCR and Western blot assay showed that expression of miR-205 was upregulated and expression of cyclin-dependent kinase 2-associated protein 1 (CDK2AP1) was downregulated in LSCC tissues. The expression levels of miR-205 were negatively related to those of CDK2AP1 in LSCC tissues and cell lines. Moreover, we found that miR-205 was the upstream regulator of CDK2AP1 and could suppress the CDK2AP1 expression in LSCC cells. 3-(4,5-dimethylthiazal-2-yl)-2,5-diphenyl-tetrazolium bromide assays and transwell invasion assay were performed to test the proliferation and invasion of LSCC cells. Gelatin zymography was used to detect the activity of MMP2 and MMP9. CDK2AP1, c-Myc and CyclinD1 expression in cells was assessed with Western blotting. We found that miR-205 was the upstream regulator of CDK2AP1 and could suppress the expression of CDK2AP1 in LSCC cells. In addition, miR-205 significantly induced cell proliferation and invasion by suppressing CDK2AP1 expression. Consistent with miR-205 inhibitors, overexpressed CDK2AP1 suppressed the activity of MMP2 and MMP9 and c-Myc and CyclinD1 expression in LSCC cells. CONCLUSION: These findings help us to better elucidate the molecular mechanisms of LSCC progression and provide a new theoretical basis to further investigate miR-205 as a potential biomarker and a promising approach for LSCC treatment.

Molecular mechanism of cisplatin to enhance the ability of TRAIL in reversing multidrug resistance in gastric cancer cells / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To study the molecular mechanism of cisplatin to enhance the ability of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in reversing multidrug resistance in vincristine-resistant human gastric cancer SGC7901/VCR cells.</p><p><b>METHODS</b>MTT assay was used to measure the 50% inhibiting concentration (IC₅₀) and cell survival in SGC7901 and SGC7901/VCR cells after different treatments. SGC7901/VCR cells were treated with different concentrations of DDP, different concentrations of TRAIL alone or in combination, and then the mRNA and protein levels of several genes were determined by RT-PCR, RT-qPCR and Western-blot analysis. After targeted silencing with specific siRNA and transfection of recombinant plasmid c-myc into the SGC7901/VCR cells, the mRNA and protein levels of DR4, DR5 and c-myc were determined by RT-PCR and Western-blot analysis.</p><p><b>RESULTS</b>After combined treatment with TRAIL and DDP of the SGC7901/VCR cells, the IC₅₀ of VCR, DDP, ADM, and 5-Fu treatment was significantly decreased compared with the control group or TRAIL-treated group (P < 0.05). After treatment with 0, 10, 50 ng/ml TRAIL in combination with 0.4 µg/ml DDP, the SGC7901/VCR cells showed significantly higher activation of caspase 3, down-regulation of DNA-PKcs/Akt/GSK-3β signaling pathway, and higher inhibition of MDR1(P-gp) and MRP1 than those treated with TRAIL alone (P < 0.01 for all). The mRNA and protein levels of DR4, DR5, c-myc were significantly decreased after silencing c-myc with specific siRNA in the SGC7901/VCR cells (P < 0.01 for all), and were significantly increased after transfection of recombinant plasmid c-myc into the SGC7901/VCR cells (P < 0.01 foe all). After the treatment with 10 ng/ml TRAIL, 0.25 µg/ml DDP + 10 ng/ml TRAIL and 0.5 µg/ml DDP + 10 ng/ml TRAIL, the relative expression level of c-myc protein in the SGC7901/VCR cells was 0.314 ± 0.012, 0.735 ± 0.026, and 0.876 ± 0.028, respectively, and the relative expression of cytochrome C was 0.339 ± 0.036, 0.593 ± 0.020 and 0.735 ± 0.031, respectively, and the relative expression levels of DR4, DR5, active-caspase 3 and active-caspase 9 in the SGC7901/VCR cells were also increased along with increasing DDP concentrations.</p><p><b>CONCLUSIONS</b>The activation of DNA-PKcs/Akt/GSK-3β signaling pathway and high expression of MDR1 and MRP1 play an important role in the multi-drug resistance properties of SGC7901/VCR cells. After combining with TRAIL, DDP can enhance the expression of DR4 and DR5 through up-regulating c-myc and enhancing the activation of caspase 3 and caspase 9 by facilitating mitochondrial release of cytochrome C. It may be an important molecular mechanism of DDP-induced sensitization of TRAIL to reverse the multidrug resistancein SGC7901/VCR cells.</p>

Prognostic analysis of BCL-2/MYC double- hit in diffuse large B-cell lymphoma / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate the effect of BCL-2/MYC double-hit on prognosis in diffuse large B-cell lymphoma（DLBCL）.</p><p><b>METHODS</b>A retrospective study was conducted to investigate clinical and pathological data of 111 patients with DLBCL. CD10, BCL-6, MUM-1, BCL-2 protein expressions were examined by immune-histochemical methods, and abnormal BCL-2 and MYC genes were analyzed by FISH for patients with sufficient pathological data. SAS 8.2 was adopted to perform Chi- square test, COX's proportional Hazard Model, Life table survival analyses.</p><p><b>RESULTS</b>Of 111 patients, male 77 cases, female 34 cases, the median age was 55（14-85）years, CD10, BCL-6, MUM-1, BCL-2 positive rates were 15.7%（16/102）, 58.8%（60/102）, 33.0%（34/103）, 74.8（77/103）respectively, the abnormal rate of BCL-2 gene was 43.1%（25/58, 24 cases with multiple copies, 1 case with translocation）, and the abnormal rate of MYC gene was 20.4%（10/49, 10 cases with multiple copies）. Coexistence of BCL-2 and MYC genes abnormalities accounted for 13.0%（6/46）. According to the classification of Hans model, GCB subgroup accounted for 41.2%（42/102）, and non-GCB subgroup 58.8%（60/102）, the median survival time was 24 months, 3-year and 5-year overall survival rates were 48.5% and 39.7% respectively. Overall survival rates of normal and abnormal BCL-2 gene were 34.2%，22.8%, respectively with no statistical significance（P=0.770）. Overall survival rates of normal and abnormal MYC gene were 35.9% and 22.2% ，with no statistical significance（P=0.650）. Overall survival rate of double-hit was 0, far worse than that of single abnormal gene（P=0.034）, which implied double-hit of BCL-2 and MYC gene abnormality to be adverse prognostic factors. BCL-6 protein express could be classified as benign prognostic factors, while ECOG score≥2, escalated IPI index as adverse prognostic factors, and further COX risk model regression analysis indicated that ECOG score, IPI grading and treatment methods were independently adverse factors affecting prognosis. Comprehensive therapy based on chemotherapy could improve outcome.</p><p><b>CONCLUSION</b>BCL-2/MYC genes double-hit was the factor for the adverse outcome in DLBCL patients. However, ECOG score, IPI risk grading and treatment methods were the independent factors affecting prognosis.</p>

Pathological diagnosis of pediatric Burkitt lymphoma involving bone marrow / 中华病理学杂志

<p><b>OBJECTIVE</b>To investigate pathologic and differential diagnostic features of pediatric Burkitt lymphoma (BL).</p><p><b>METHODS</b>A total of 20 cases of pediatric BL were retrospectively reviewed for their clinical and pathologic profiles. Bone marrow aspiration specimens were available in all cases and bone marrow biopsies were available for immunohistochemical study in 18 cases. Flow cytometry study was available in 16 cases. MYC translocation by FISH method was performed in 11 cases.</p><p><b>RESULTS</b>Atypical lymphocytes with cytoplasmic vacuoles were found in bone marrow smears in all 20 cases and peripheral blood films in all 19 available cases. The bone marrow biopsies showed infiltration by uniform medium-sized atypical lymphocytes with multiple small nucleoli but without the starry-sky pattern in all 18 cases. Immunohistochemistry showed the following results in all 18 cases: positive for CD20, PAX-5, CD10, CD34 and TdT, but negative for bcl-2 and CD3 with Ki-67 > 95%.Flow cytometry showed CD19+CD20+CD10+FMC7+CD22+TdT-CD3- in 16 cases, including κ+ in 8 cases, λ+ in 7 cases, and κ-λ- in 1 case. MYC gene rearrangement by FISH was observed in 10 of the 11 cases.</p><p><b>CONCLUSIONS</b>The histopathology of BL is distinct, including atypical lymphocytes with cytoplasmic vacuoles in bone marrow aspirate, lack of starry-sky patternin bone marrow biopsy. Generally, the diagnosis should be made with a combined immunophenotype and FISH approach. Pediatric BL must be distinguished from DLBCL and B-cell lymphoma, unclassifiable, which has intermediate features between DLBCL and Burkitt lymphoma.</p>