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1.
Leuk Res ; 83: 106159, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31228652

RESUMO

Genomic profiles of leukemia patients lead to characterization of variations that provide the molecular classification of risk groups, prediction of clinical outcome and therapeutic decisions. In this study, we examined the diagnostic (n = 77) and relapsed (n = 31) pediatric B-cell acute lymphoblastic leukemia (B-ALL) samples for the most common leukemia-associated gene variations CRLF2, JAK2, PAX5 and IL7R using deep sequencing and copy number alterations (CNAs) (CDKN2A/2B, PAX5, RB1, BTG1, ETV6, CSF2RA, IL3RA and CRLF2) by multiplex ligation proximity assay (MLPA), and evaluated for the clonal changes through relapse. Single nucleotide variations SNVs were detected in 19% of diagnostic 15.3% of relapse samples. The CNAs were detected in 55% of diagnosed patients; most common affected genes were CDKN2A/2B, PAX5, and CRLF2. Relapse samples did not accumulate a greater number of CNAs or SNVs than the cohort of diagnostic samples, but the clonal dynamics showed the accumulation/disappearance of specific gene variations explained the course of relapse. The CDKN2A/2B were most frequently altered in relapse samples and 32% of relapse samples carried at least one CNA. Moreover, CDKN2A/2B alterations and/or JAK2 variations were associated with decreased relapse-free survival. On the other hand, CRLF2 copy number alterations predicted a better survival rate in B-ALL. These findings contribute to the knowledge of CDKN2A/2B and CRLF2 alterations and their prognostic value in B-ALL. The integration of genomic data in clinical practice will enable better stratification of ALL patients and allow deeper understanding of the nature of relapse.

2.
Turk J Haematol ; 36(3): 178-185, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31042345

RESUMO

Objective: Angiotensin II promotes growth and angiogenesis via type 1 receptors (AGTR1) in certain tumors. In this study, we examine the bone marrow AGTR1 expression in multiple myeloma (MM) and its relationship with the regulation of angiogenesis and prognostic factors. Materials and Methods: Bone marrow AGTR1 mRNA levels of 39 MM patients and 15 healthy controls were analyzed with quantitative RT-PCR. Immunohistochemical staining of the tissue vascular endothelial growth factor (VEGF), CD34, and factor VIIIrAg (fVIIIrAg) was used to assess bone marrow angiogenesis. Results: Bone marrow samples of the patients showed increased VEGF, fVIIIrAg, and CD34 staining and higher AGTR1 expression levels when compared to controls. Patients with severe-diffuse bone marrow infiltration showed higher bone marrow VEGF, fVIIIrAg, CD34, and AGTR1 mRNA levels when compared to other patients. Conclusion: AGTR1 expression was found positively correlated with plasma ß2-microglobulin level and patients with increased AGTR1 expression showed increased bone marrow CD34 levels.

4.
Leuk Lymphoma ; : 1-9, 2018 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-29965782

RESUMO

Tyrosine kinase inhibitor (TKI) therapy is the current treatment of choice for patients with chronic phase chronic myeloid leukemia (CML) leading to rapid and durable hematological as well as molecular responses. However, emergence of resistance to TKIs has been the major obstacle to treatment success on long term. In this regard kinase domain mutations are the most common mechanism of therapy failure. In this study, we analyzed peripheral blood samples from 17 CML patients who had developed resistance to various TKIs by using next-generation sequencing parallel to Sanger sequencing. BCR-ABL1 kinase domain mutations have been found in 59% of the cohort. Our results demonstrate that next-generation sequencing results in a higher mutational detection rate than reported with conventional sequencing methodology. Furthermore, it showed the clonal diversity more accurately.

5.
Pituitary ; 21(4): 335-346, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29455389

RESUMO

OBJECTIVE: To determine aryl hydrocarbon interacting protein (AIP) gene variations and AIP and somatostatin receptor (SSTR) 1-5 immunostaining in patients with apparently sporadic acromegaly with poor versus good response to somatostatin analogues (SRLs). METHODS: A total of 94 patients (66 with poor and 28 with good response to SRLs) were screened for the AIP gene variations using Sanger sequencing. Immunostaining was performed in 60 tumors. RESULTS: Several variations, albeit some with undetermined significance, were detected, especially in poor responder patients. The prevalence of AIP mutation was 2.1% in the whole group and 1.5% in patients with poor response to SRLs. AIP, SSTR2A, and SSTR2B immunostainings were decreased in patients with poor response (p < 0.05 for all), and other SSTRs did not differ between the groups (p > 0.05 for all). Patients with low AIP had decreased levels of SSTR2A and SSTR3 (p < 0.05 for all). AIP and SSTR2A immunostainings were positively correlated to the treatment response and age at diagnosis was negatively correlated (p < 0.05 for all). In poor responder patients with high SSTR2A immunostaining, SSTR2B immunostaining and preoperative tumor size were positively and negatively correlated, respectively, to SRL response (p < 0.05 for all). CONCLUSIONS: Lack of response to SRLs does not necessarily increase the risk of harboring AIP mutations. The finding of decreased AIP, SSTR2A, and SSTR2B immunostaining in patients with poor response to SRLs and decreased SSTR2A and SSTR3 level in those with low AIP immunostaining suggests a possible interaction between AIP and some SSTR subtypes that might alter SRL sensitivity.


Assuntos
Acromegalia/tratamento farmacológico , Acromegalia/genética , Mutação em Linhagem Germinativa/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Receptores de Somatostatina/genética , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Adulto , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade
6.
Immunogenetics ; 69(10): 653-659, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28597365

RESUMO

Severe combined immunodeficiency (SCID) is the most severe form of primary immunodeficiency, which is characterized by the dysfunction and/or absence of T lymphocytes. Early diagnosis of SCID is crucial for overall survival, and if it remains untreated, SCID is often fatal. Next-generation sequencing (NGS) has become a rapid, high-throughput technology, and has already been proven to be beneficial in medical diagnostics. In this study, a targeted NGS panel was developed to identify the genetic variations of SCID by using SmartChip-TE technology, and a novel pathogenic frameshift variant was found in the CD3E gene. Sanger sequencing has confirmed the segregation of the variant among patients. We found a novel deletion in the CD3E gene (NM000733.3:p.L58Hfs*9) in two T-B+ NK+ patients. The variant was not found in the databases of dbSNP, ExAC, and 1000G. One sibling in family I was homozygous and the rest of the family members were heterozygous for this variant. T cell receptor excision circle (TREC) and kappa-deleting recombination excision circle (KREC) analyses were performed for T and B cell maturation. TRECs were not detected in both patients and the KREC copy numbers were similar to the other family members. In addition, heterozygous family members showed decreased TREC levels when compared with the wild-type sibling, indicating that carrying this variant in one allele does not cause immunodeficiency, but does effect T cell proliferation. Here, we report a novel pathogenic frameshift variant in CD3E gene by using targeted NGS panel.


Assuntos
Sequência de Bases , Complexo CD3/genética , Mutação da Fase de Leitura , Deleção de Sequência , Imunodeficiência Combinada Severa/genética , Linfócitos B/imunologia , Linfócitos B/patologia , Complexo CD3/imunologia , Proliferação de Células , Consanguinidade , Feminino , Expressão Gênica , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Lactente , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Masculino , Linhagem , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/patologia , Irmãos , Linfócitos T/imunologia , Linfócitos T/patologia , Turquia
7.
Turk J Med Sci ; 47(1): 357-363, 2017 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-28263515

RESUMO

BACKGROUND/AIM: The canonical Wingless-type (WNT) pathway is involved in normal hematopoietic cell development and deregulated WNT signaling is implicated in the development of hematological malignancies. Dickkopf 1 (DKK1) acts as a modulator of the ß-catenin regulated canonical pathway. Activation of DKK1 leads to apoptosis and growth suppression, whereas silencing by promoter hypermethylation results in abnormal WNT activation. The secreted inhibitor Dickkopf can antagonize WNT signaling by competitively binding to low density lipoprotein receptors (LRPs) 5 and 6. MATERIALS AND METHODS: We studied DKK1 gene promoter methylation and investigated DKK1, ß-catenin, LRP5, and LRP6 mRNA levels in B-cell acute lymphoblastic leukemia (B-ALL) patients (n = 90). Methylation-specific PCR and bisulfite sequencing were used for methylation profiling and quantitative real-time PCR was used for mRNA detection. RESULTS: The DKK1 gene was examined for its promoter methylation and only 33% of patients were found methylated. On the other hand, B-ALL cases showed high expression of DKK1 (P = 0.01), LRP5 (P = 0.04), and LRP6 (P = 0.02) compared to normal bone marrow cells. CONCLUSION: DKK1 methylation exists in some of cases but is not sufficient for WNT pathway activation alone in pediatric B-ALL.

8.
Turk J Haematol ; 33(3): 172-9, 2016 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-27507302

RESUMO

Novel high-throughput sequencing technologies generate large-scale genomic data and are used extensively for disease mapping of monogenic and/or complex disorders, personalized treatment, and pharmacogenomics. Next-generation sequencing is rapidly becoming routine tool for diagnosis and molecular monitoring of patients to evaluate therapeutic efficiency. The next-generation sequencing platforms generate huge amounts of genetic variation data and it remains a challenge to interpret the variations that are identified. Such data interpretation needs close collaboration among bioinformaticians, clinicians, and geneticists. There are several problems that must be addressed, such as the generation of new algorithms for mapping and annotation, harmonization of the terminology, correct use of nomenclature, reference genomes for different populations, rare disease variant databases, and clinical reports.


Assuntos
Variação Genética/genética , Sequenciamento de Nucleotídeos em Larga Escala , Algoritmos , Interpretação Estatística de Dados , Bases de Dados Genéticas , Humanos
9.
Turk J Haematol ; 32(2): 127-35, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26316480

RESUMO

OBJECTIVE: WNT5A is one of the most studied noncanonical WNT ligands and is shown to be deregulated in different tumor types. Our aim was to clarify whether hypermethylation might be the cause of low WNT5A mRNA levels and whether we could restore this downregulation by reversing the event. MATERIALS AND METHODS: The expression of WNT5A mRNA was studied in a large acute lymphoblastic leukemia (ALL) patient group (n=86) by quantitative real-time PCR. The methylation status was detected by methylation-specific PCR (MSPCR) and bisulphate sequencing. In order to determine whether methylation has a direct effect on WNT5A expression, disease-representative cell lines were treated by 5'-aza-20-deoxycytidine. RESULTS: Here we designed a validation experiment of the WNT5A gene, which was previously examined and found to be differentially expressed by microarray study in 31 T-cell ALL patients. The expression levels were confirmed by quantitative real-time PCR and the expression levels were significantly lower in T-cell ALL patients than in control thymic subsets (p=0.007). MSPCR revealed that 86% of the patients were hypermethylated in the WNT5A promoter region. Jurkat and RPMI cell lines were treated with 5'-aza-20-deoxycytidine and WNT5A mRNA expression was restored after treatment. CONCLUSION: According to our results, WNT5A hypermethylation does occur in ALL patients and it has a direct effect on mRNA expression. Our findings show that epigenetic changes of WNT signaling can play a role in ALL pathogenesis and reversing methylation might be useful as a possible treatment of leukemia.


Assuntos
Metilação de DNA , Proteínas de Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Regiões Promotoras Genéticas/genética , Proteína Wnt-5a/genética , Adolescente , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Linhagem Celular Tumoral , Criança , Pré-Escolar , Decitabina , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lactente , Recém-Nascido , Células Jurkat , Masculino , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/fisiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Via de Sinalização Wnt/fisiologia , Proteína Wnt-5a/biossíntese , Proteína Wnt-5a/fisiologia
10.
Cytotechnology ; 67(6): 1003-9, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24828824

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common cancers, which may lead to death. Menadione shows cytotoxic activity thought affecting redox cycling in cancer cells. The aim of the present study was to investigate the effects of menadione on rat hepatocellular carcinoma (H4IIE) cell morphology, cytotoxicity, apoptosis and DNA damage or repair in vitro. Cell morphology evaluated by microscopy and cell viability was determined using the 3-[4,5-dimethylthiazol-2yl]-diphenyltetrazolium bromide test. Apoptotic cell death was assessed in H4IIE cells treated with menadione by 4',6-diamidino-2-phenylindole staining. Quantitative real time polymerase chain reaction used to determine the expression level of poly (ADP-ribose) polymerase 1 (PARP1) gene. According to the results of this study menadione has got a cytotoxic activity (IC50 25 µM) and change the cell fate in H4IIE cells. Menadione treatments lead to PARP1 activation in a dose dependent manner and induce DNA damage and apoptosis, and this may suggest its use as a therapeutic agent in HCC treatment.

11.
Turk J Haematol ; 31(2): 136-42, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25035670

RESUMO

OBJECTIVE: The prominent functions of the local renin-angiotensin system (RAS) in primitive hematopoiesis further support the hypothesis that local autocrine bone marrow RAS could also be active in neoplastic hematopoiesis. The aim of this study is to examine critical RAS elements in normal CD34+ hematopoietic stem cells and multiple myeloma (MM)-related progenitor cells. MATERIALS AND METHODS: The study group comprised the total bone marrow cells (CBM) of 10 hematologically normal people, the CD34+ stem cell samples (CD34+CBM) of 9 healthy donors for allogeneic peripheral stem cell transplantation, and the CD34+ stem cell samples (CD34+MM) of 9 MM patients undergoing autologous peripheral stem cell transplantation. We searched for the gene expression of the major RAS components in healthy hematopoietic cells and myeloma cells by quantitative real-time polymerase chain reaction analysis. RESULTS: RENIN, angiotensinogen (ANGTS), and angiotensin converting enzyme-I (ACE I) mRNA expression levels of CBM were significantly higher than those in myeloma patients (p=0.03, p=0.002, and p=0.0008, respectively). Moreover, RENIN and ANGTS mRNA expression levels were significantly higher in CD34+ stem cell samples of healthy allogeneic donors compared to those in myeloma patients (p=0.001 and p=0.01). However, ACE I expression levels were similar in CD34+CBM and CD34+MM hematopoietic cells (p=0.89). CONCLUSION: Although found to be lower than in the CBM and CD34+CBM hematopoietic cells, the local RAS components were also expressed in CD34+MM hematopoietic cells. This point should be kept in mind while focusing on the immunobiology of MM and the processing of autologous cells during the formation of transplantation treatment protocols.

12.
Int J Clin Exp Med ; 7(1): 280-4, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24482717

RESUMO

Permanent hypoparathyroidism is a serious clinical situation. Allotransplantation of the parathyroid cells is relatively new approach to treatment. Non-cultivated allotransplantation in rabbits is not tried before. In this research parathyroidectomy was performed in six female New Zealand white rabbits. After division of surgically removed tissues into two, cryopreservation after cell isolation was done. Non-cultivated cross allotransplantation was performed under immunosuppression. Serum calcium and phosphorus levels were observed 15 days and histopathological analyses of the transplanted parathyroid tissues were studied. Significant changes in serum calcium and phosphorus levels during the experiment were observed (p=0.001 for both). Calcium levels which were significantly dropped to 6.66±0.7 mg/dL after parathyroidectomy and progressively increased up to 15.98±1.25 mg/dL at the end of the experiment (p=0.004). Phosphorus levels which were increased to 9.38±0.63 mg/dL after parathyroidectomy and stabilized to 4.46±1.06 mg/dL at the end of the experiment (p=0.007). All allotransplanted parathyroid tissues showed normal tissue architecture without evidence of cellular rejection. In conclusion allotransplantation of the parathyroid tissues without cultivation may be considered as an alternative and safe approach for the treatment of permanent hypoparathyroidism.

13.
Hum Genome Var ; 1: 14016, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-27081507

RESUMO

Poly(ADP-ribose) polymerase-1 (PARP-1) has a vital role in the progression of the inflammatory response, and its inhibition confers protection in various models of inflammatory disorders. Therefore, we investigated the effect of promoter and exon variations of the PARP-1 gene on the risk for the inflammatory disease Hashimoto's thyroiditis (HT). This case-control association study was comprised of 141 HT patients and 150 controls from a group of women in a Turkish population. Two polymorphisms in the promoter region of the PARP-1 gene, rs2793378 and rs7527192, were analyzed using the PCR-RFLP method. In addition, single nucleotide polymorphism (SNP) rs1136410, which is located at codon 762, was analyzed using bidirectional sequencing. The combined genotype and haplotype analyses of these polymorphisms were performed using SPSS 18 and Haploview 4.2. The results were statistically analyzed by calculating the odds ratios and 95% confidence interval using Pearson's χ (2)-test and Fisher's exact test (two-sided). Although we had a number of significant results, the associations became nonsignificant following a Bonferroni correction for multiple comparisons. Nonetheless, a protective factor against HT was still observed for the heterozygous genotype (TC) of SNP rs1136410 (P=0.001), even following Bonferroni correction, and according to the rs2793378-rs7527192 combined analysis, the occurrence of the TT/GA combined genotype was significantly higher in the controls (P=0.007). These results prove that the heterozygosity of SNP rs1136410 provides a protective effect against HT disease in a group of women in a Turkish population.

14.
Pituitary ; 17(3): 220-6, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23743763

RESUMO

Aryl hydrocarbon receptor-interacting protein (AIP) is associated with 15-20% of familial isolated pituitary adenomas and 50-80% of cases with AIP mutation exhibit a somatotropinoma. Herein we report clinical characteristics of a large family where AIP R304X variants have been identified. AIP mutation analysis was performed on a large (n = 52) Turkish family across six generations. Sella MRIs of 30 family members were obtained. Basal pituitary hormone levels were evaluated in 13 family members harboring an AIP mutation. Thirteen of 52 family members (25%) were found to have a heterozygous nonsense germline R304X mutation in the AIP gene. Seven of the 13 mutation carriers (53.8%) had current or previous history of pituitary adenoma. Of these 7 mutation carriers, all but one had somatotropinoma/somatolactotropinoma (85.7% of the pituitary adenomas). Of the 6 acromegaly patients with AIP mutation (F/M: 3/3) the mean age at diagnosis of acromegaly was 32 ± 10.3 years while the mean age of symptom onset was 24.8 ± 9.9 years. Three of the six (50%) acromegaly cases with AIP mutation within the family presented with a macroadenoma and none presented with gigantism. Biochemical disease control was achieved in 66.6% (4/6) of the mutation carriers with acromegaly after a mean follow-up period of 18.6 ± 17.6 years. Common phenotypic characteristics of familial pituitary adenoma or somatotropinoma due to AIP mutation vary between families or even between individuals within a family.


Assuntos
Acromegalia/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Hipofisárias/genética , Adolescente , Adulto , Idoso , Estudos de Coortes , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Linhagem , Hormônios Hipofisários/sangue , Turquia , Adulto Jovem
15.
J Renin Angiotensin Aldosterone Syst ; 14(4): 308-14, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23132846

RESUMO

There is preliminary evidence that the local renin-angiotensin system (RAS) could affect neoplastic hematopoiesis. The aim of this study is to search messenger RNA (mRNA) expressions of the essential RAS elements in myeloid and lymphoid hematological neoplastic disorders. Forty-six patients with newly diagnosed myeloid (AML, biphenotypic leukemia, CML) or lymphoid (CLL, NHL, B-ALL, T-ALL) hematological disorders were included in the study. In the lymphoid group, the median expression values of RENIN, ACE1, ACE2 and ANGIOTENSINOGEN (ANGTS) mRNAs were 1.96%, 0.42%, 0.00% and 0.00%, respectively; in the myeloid group, 0.73%, 1.55%, 0.04% and 0.006%, respectively. In the lymphoid group, RENIN levels were significantly higher (p = 0.001), whereas ACE1 and ACE2 levels were significantly higher in the myeloid group (p values were 0.013 and 0.010, respectively). ANGTS levels were similar in both groups. In patients with non-ALL lymphoid malignancies, RENIN expressions were significantly higher when compared to ALL patients (p = 0.004). All patients with active disease had significantly higher RENIN mRNA expression levels than patients without active disease (2.03% vs 0.30%) (p = 0.034). The result of our present study indicates that the activities of local RAS may differ in distinct disease states such as leukemia and lymphomas.


Assuntos
Neoplasias Hematológicas/metabolismo , Hematopoese , Linfoma/metabolismo , Sistema Renina-Angiotensina , Angiotensinogênio/genética , Angiotensinogênio/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Renina/genética , Renina/metabolismo
16.
Br J Haematol ; 158(5): 626-34, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22775572

RESUMO

TRIB2 is a potent oncogene, elevated in a subset of human acute myeloid leukaemias (AML) with a mixed myeloid/lymphoid phenotype and NOTCH1 mutations. Although rare in AML, activating NOTCH1 mutations occur in 50% of all T cell acute lymphoblastic leukaemias (T-ALL). TRIB2 is a NOTCH1 target gene that functions in the degradation of key proteins and modulation of MAPK signalling pathways, implicated in haematopoietic cell survival and proliferation. This study showed that TRIB2 expression level is highest in the lymphoid compartment of normal haematopoietic cells, specifically in T cells. Analysis of TRIB2 expression across 16 different subtypes of human leukaemia demonstrated that TRIB2 expression was higher in ALL phenotypes versus all other phenotypes including AML, chronic lymphocytic leukaemia (CLL), myelodysplastic syndrome (MDS) and chronic myeloid leukaemia (CML). A T cell profile was distinguished by high TRIB2 expression in normal and malignant haematopoiesis. High TRIB2 expression was seen in T-ALL with normal karyotype and correlated with NOTCH signalling pathways. High TRIB2 expression correlated with NOTCH1/FBXW7 mutations in a paediatric T-ALL cohort, strongly linking NOTCH1 activation and high TRIB2 expression in paediatric T-ALL. The relationship between TRIB2 and T cell signalling pathways uniquely identifies leukaemia subtypes and will be useful in the advancement of our understanding of T cell and ALL biology.


Assuntos
Hematopoese/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Receptor Notch1/metabolismo , Adolescente , Proteínas Quinases Dependentes de Cálcio-Calmodulina , Proteínas de Ciclo Celular/genética , Criança , Pré-Escolar , Proteínas F-Box/genética , Proteína 7 com Repetições F-Box-WD , Feminino , Humanos , Lactente , Recém-Nascido , Peptídeos e Proteínas de Sinalização Intracelular/genética , Cariótipo , Masculino , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptor Notch1/genética , Transdução de Sinais , Linfócitos T/metabolismo , Ubiquitina-Proteína Ligases/genética , Adulto Jovem
18.
Leuk Res ; 36(1): 87-92, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21813177

RESUMO

B-lineage acute lymphoblastic leukemia (B-ALL) is a common subtype of acute leukemia in children. PAX5 plays a central role in B-cell development and differentiation. In this study, we analyzed PAX5 expression levels, transactivation domain mutations/deletions in B-ALL patients (n=115) and healthy controls (n=10). Relative PAX5 mRNA levels were significantly increased in B-ALL patients (p<0.0001). PAX5 expression was also evaluated in three different B-ALL subgroups (pro B, Common B and Pre B ALL) and showed stage specific expression levels. Pro B (p=0.04) and pre B (p=0.04) patients showed significantly high PAX5 mRNA levels compared to stage specific controls. At least one deletion of exons 7-8 or 9 has been identified in the 41% of the patients. CD34 positivity in patients and presence of large deletions (Δ7/8/9) showed a significant correlation (p=0.05). None of our patients showed PAX5 point mutations, but two previously identified SNPs (rs3780135 and rs35469494) were detected. Our results support that PAX5 is a critical factor in B-ALL development and aberrant PAX5 expression especially at early stages may leads to leukemic transformation.


Assuntos
Linfócitos B/metabolismo , Fator de Transcrição PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Linfócitos B/patologia , Linhagem Celular , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Regulação Leucêmica da Expressão Gênica , Humanos , Lactente , Masculino , Mutação , Estadiamento de Neoplasias , Fator de Transcrição PAX5/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo
19.
Turk J Haematol ; 29(4): 325-33, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24385720

RESUMO

OBJECTIVE: T-cell acute lymphoblastic leukemia (T-ALL) is associated with recurrent chromosomal aberrations andabnormal ectopic gene expression during T-cell development. In order to gain insight into the pathogenesis of T-ALLthis study aimed to measure the level of expression of 7 T-cell oncogenes (LMO2, LYL1, TAL1, TLX1, TLX3, BMI1, andCALM-AF10) in pediatric T-ALL patients Material and Methods: LMO2, LYL1, TLX1, TLX3, BMI1, TAL1, and CALM-AF10 expression was measured usingquantitative real-time PCR in 43 pediatric T-ALL patients. RESULTS: A high level of expression of LMO2, LYL1, TAL1, and BMI1 genes was observed in a large group of T-ALL.Several gene expression signatures indicative of leukemic arrest at specific stages of normal thymocyte development(LYL1 and LMO2) were highly expressed during the cortical and mature stages of T-cell development. Furthermore,upregulated TAL1 and BMI1 expression was observed in all phenotypic subgroups. In all, 6 of the patients had TLX1and TLX3 proto-oncogene expression, which does not occur in normal cells, and none of the patients had CALM-AF10fusion gene transcription. Expression of LYL1 alone and LMO2-LYL1 co-expression were associated with mediastinalinvolvement; however, high-level oncogene expression was not predictive of outcome in the present pediatric T-ALLpatient group, but there was a trend towards a poor prognostic impact of TAL1 and/or LMO2 and/or LYL1 protooncogeneexpression. CONCLUSION: Poor prognostic impact of TAL1 and/or LMO2 and/or LYL1 proto-oncogene expression indicate the needfor extensive study on oncogenic rearrangement and immunophenotypic markers in T-ALL, and their relationship totreatment outcome. CONFLICT OF INTEREST: None declared.

20.
Anadolu Kardiyol Derg ; 11(4): 319-28, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21561848

RESUMO

OBJECTIVE: Atrial isomerism is a congenital disorder, which is characterized by lateralization defects in normally asymmetrical developing organs like the heart. Atrial isomerism is supposed to be caused by molecular defects during early development. The NKX2-5 is a cardiac specific transcription factor, which initiates and regulates downstream transcriptional cascades of cardiogenesis. The HAND1 is another transcription factor expressed in the heart, and it is characterized by an asymmetrical pattern of expression. In this study, we aimed to test whether mutations in NKX2-5 and HAND1 genes play a role in the etiology of atrial isomerism. METHODS: This case-control study consisted of 70 patients who underwent surgical treatment for congenital heart defects including atrial isomerism, 80 healthy subjects (HAND1 gene) and 40 healthy subjects (NKX2-5 gene). All exons and exon-intron boundaries of NKX2-5 and HAND1 genes were analyzed by SSCP, and suspected samples were sequenced for mutation analysis. Digestion with appropriate restriction enzymes was performed for analysis of known mutations and polymorphisms. The frequencies of the alleles and the genotypes were compared among patient and control groups using the Chi-square and the Fisher tests when appropriate. RESULTS: In intronic region of HAND1 gene, we identified a C>G substitution both in patients and controls. Frequency of mutant allele (11, 42%) was found higher (p=0.046) in patient group than that of the control group (2.5%). Association between atrial isomerism and genotypes with mutant allele was found borderline significant (p=0.054). In NKX2-5 gene, we identified heterozygous Q170X (Gln170ter) mutation in one patient. We did not found any correlation between defined sequence variations and clinical properties of the patients. CONCLUSION: Our results suggest that mutations or sequence variations in HAND1 or NKX2-5 genes may play role in etiology or pathogenesis of atrial isomerism.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Átrios do Coração/anormalidades , Cardiopatias Congênitas/genética , Proteínas de Homeodomínio/genética , Fatores de Transcrição/genética , Estudos de Casos e Controles , Primers do DNA , Feminino , Proteína Homeobox Nkx-2.5 , Humanos , Masculino , Mutação , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição
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