Fabiola Traina

University of São Paulo, San Paulo, São Paulo, Brazil

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Publications (83)258.72 Total impact

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    ABSTRACT: Vasodilator-stimulated phosphoprotein (VASP) and Zyxin are interacting proteins involved in cellular adhesion and motility. PKA phosphorylates VASP at serine 157, regulating VASP cellular functions. VASP interacts with ABL and is a substrate of the BCR-ABL oncoprotein. The presence of BCR-ABL protein drives oncogenesis in patients with chronic myeloid leukemia (CML) due to a constitutive activation of tyrosine kinase activity. However, the function of VASP and Zyxin in BCR-ABL pathway and the role of VASP in CML cells remain unknown. In vitro experiments using K562 cells showed the involvement of VASP in BCR-ABL signaling. VASP and Zyxin inhibition decreased the expression of anti-apoptotic proteins, BCL2 and BCL-XL. Imatinib induced an increase in phosphorylation at Ser157 of VASP and decreased VASP and BCR-ABL interaction. VASP did not interact with Zyxin in K562 cells; however, after Imatinib treatment, this interaction was restored. Corroborating our data, we demonstrated the absence of phosphorylation at Ser157 in VASP in the bone marrow of CML patients, in contrast to healthy donors. Phosphorylation of VASP on Ser157 was restored in Imatinib responsive patients though not in the resistant patients. Therefore, we herein identified a possible role of VASP in CML pathogenesis, through the regulation of BCR-ABL effector proteins or the absence of phosphorylation at Ser157 in VASP. Copyright © 2014. Published by Elsevier B.V.
    Biochimica et biophysica acta. 11/2014;
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    ABSTRACT: TET2, a member of the ten-eleven-translocation (TET) family genes that modify DNA by converting 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), is located in chromosome 4q24, and is frequently mutated in myeloid malignancies. The impact of TET2 mutation on survival outcomes is still controversial, however functional studies have proved that it is a loss-of-function mutation that impairs myeloid cell differentiation and contributes to the phenotype of myeloid neoplasia. We, herein, aimed to investigate TET2 expression in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients. A significantly decreased TET2 expression was observed in bone marrow cells from AML (n=53) and MDS (n=64) patients, compared to normal donors (n=22). In MDS, TET2 expression was significantly reduced in RAEB1/RAEB-2 compared to other WHO 2008 classifications, and a lower TET2 expression was observed at the time of MDS disease progression in 4 out of 5 patients. In multivariate analysis, low TET2 expression (p<.03), male gender (p<.03) and WHO 2008 classification (p<.0001) were independent predictors of poorer overall survival. These results suggest that defective TET2 expression plays a role in the MDS pathophysiology and predicts survival outcomes in this disease.This article is protected by copyright. All rights reserved.
    European Journal Of Haematology 09/2014; · 2.55 Impact Factor
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    ABSTRACT: Mastocytosis are myeloproliferative neoplasms commonly related to gain-of-function mutations involving the tyrosine kinase domain of KIT. We herein report a case of familial systemic mastocytosis with the rare KIT K509I germ line mutation affecting two family members: mother and daughter. In vitro treatment with imatinib, dasatinib and PKC412 reduced cell viability of primary mast cells harboring KIT K509I mutation. However, imatinib was more effective in inducing apoptosis of neoplastic mast cells. Both patients with familial systemic mastocytosis had remarkable hematological and skin improvement after three months of Imatinib treatment, suggesting that it may be an effective front line therapy for patients harboring KIT K509I mutation.
    Leukemia Research 08/2014; · 2.76 Impact Factor
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    ABSTRACT: Pyrimidine-5'-nucleotidase type I (P5'NI) deficiency is an autosomal recessive condition that causes nonspherocytic hemolytic anemia, characterized by marked basophilic stippling and pyrimidine nucleotide accumulation in erythrocytes. We herein present two African descendant patients, father and daughter, with P5'N deficiency, both born from first cousins. Investigation of the promoter polymorphism of the uridine diphospho glucuronosyl transferase 1A (UGT1A) gene revealed that the father was homozygous for the allele (TA7) and the daughter heterozygous (TA6/TA7). P5'NI gene (NT5C3) gene sequencing revealed a further change in homozygosity at amino acid position 56 (p.R56G), located in a highly conserved region. Both patients developed gallstones; however the father, who had undergone surgery for the removal of stones, had extremely severe intrahepatic cholestasis and, liver biopsy revealed fibrosis and siderosis grade III, leading us to believe that the homozygosity of the UGT1A polymorphism was responsible for the more severe clinical features in the father. Moreover, our results show how the clinical expression of hemolytic anemia is influenced by epistatic factors and we describe a new mutation in the P5'N gene associated with enzyme deficiency, iron overload, and severe gallstone formation. To our knowledge, this is the first description of P5'N deficiency in South Americans.
    Blood Cells Molecules and Diseases 08/2014; · 2.26 Impact Factor
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    ABSTRACT: Although myelodysplastic syndromes have a clear definition in theory, the morphologic dysplasia associated with ineffective hematopoiesis may be subtle and difficult to recognize and can commonly be mimicked by systemic conditions, such as infections, autoimmune disorders, nutritional deficiencies, toxic factors and non-hematological malignancies. However, myelodysplastic syndromes may truly coexist with other systemic diseases, which can be masked when the patient's symptoms are attributed exclusively to myelodysplastic syndromes without further investigation. To better illustrate this, we herein describe two cases associated with synchronous gastric cancers.
    Revista Brasileira de Hematologia e Hemoterapia 07/2014;
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    ABSTRACT: Review on SIVA1, with data on DNA/RNA, on the protein encoded and where the gene is implicated.
    Atlas of Genetics and Cytogenetics in Oncology and Haematology. 04/2014; 18(5):334-339.
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    ABSTRACT: ANKHD1 is a multiple ankyrin repeat containing protein, recently identified as a novel member of the Hippo signaling pathway. The present study aimed to investigate the role of ANKHD1 in DU145 and LNCaP prostate cancer cells. ANKHD1 and YAP1 were found to be highly expressed in prostate cancer cells, and ANKHD1 silencing decreased cell growth, delayed cell cycle progression at the S phase, and reduced tumor xenograft growth. Moreover, ANKHD1 knockdown downregulated YAP1 expression and activation, and reduced the expression of CCNA2, a YAP1 target gene. These findings indicate that ANKHD1 is a positive regulator of YAP1 and promotes cell growth and cell cycle progression through Cyclin A upregulation.
    Experimental Cell Research 04/2014; · 3.56 Impact Factor
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    ABSTRACT: Stathmin 1 is a microtubule destabilizer that plays an important role in cell cycle progression, segregation of chromosomes, clonogenicity, cell motility and survival. Stathmin 1 overexpression has been reported in malignant hematopoietic cells and Stathmin 1 inhibition reduces the highly proliferative potential of leukemia cell lines. However, during the differentiation of primary hematopoietic cells, Stathmin 1 expression decreases in parallel to decreases in the proliferative potential of early hematopoietic progenitors. The scope of the present review is to survey the current knowledge and highlight future perspectives for Stathmin 1 in normal and malignant hematopoiesis, with regard to the expression, function and clinical implications of this protein.
    BMB reports 03/2014; · 1.63 Impact Factor
  • Leukemia & lymphoma 03/2014; · 2.61 Impact Factor
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    ABSTRACT: Myelodysplastic syndromes (MDS) are clonal disorders involving hematopoietic stem cells (HSC) characterized by ineffective hematopoiesis. In addition to HSC defects, a defective hematopoiesis supporting capacity of mesenchymal stromal cells (MSC) in the microenvironment niche has been implicated in MDS pathophysiology. The interaction between the dysfunctional MSC MDS and HSC regulates diverse adhesion-related processes, such as progenitor cell survival, proliferation, differentiation and self-renewal. As previously reported, a microarray analysis identified SPINT2, an inhibitor of HGF activation, to be downregulated in MSC from MDS patients. To define the role of SPINT2 in MDS hematopoietic microenvironment, an analysis of the effect of SPINT2 silencing in MSC was carried out. We herein reported significantly lower levels of SPINT2 whereas HGF was expressed at higher levels in MSC from MDS patients compared to healthy controls. SPINT2 underexpression results in an increased expression, production and secretion of HGF and SDF-1 by MSC. An increased adhesion of normal HSC or malignant cells onto mesenchymal stromal cells silenced for SPINT2 was also observed. The altered MSC adhesion in SPINT2 knockdown cells was correlated with increased CD49b and CD49d expressions and with a decrease in CD49e expression. Our results suggest that the SPINT2 underexpression in the mesenchymal stromal cells from MDS patients is probably involved in the adhesion of progenitors to the bone marrow niche, through an increased HGF and SDF-1 signaling pathway.
    Stem cells and development 01/2014; · 4.15 Impact Factor
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    ABSTRACT: Recently, a novel CXCL12-binding receptor, has been identified. This CXCL12-binding receptor commonly known as CXCR7 (CXC chemokine receptor 7), has lately, based on a novel nomenclature, has received the name ACKR3 (atypical chemokine receptor 3). In this study, we aimed to investigate the expression of CXCR7 in leukemic cells, as well as its participation in CXCL12 response. Interesting, we clearly demonstrated that CXCR7 is highly expressed in acute lymphoid leukemic cells compared with myeloid or normal hematopoietic cells and that CXCR7 contributed to T-acute lymphoid leukemic cell migration induced by CXCL12. Moreover, we showed that the cellular location of CXCR7 varied among T-lymphoid cells and this finding may be related to their migration capacity. Finally, we hypothesized that CXCR7 potentiates CXCR4 response and may contribute to the maintenance of leukemia by initiating cell recruitment to bone marrow niches that were once occupied by normal hematopoietic stem cells.
    PLoS ONE 01/2014; 9(1):e85926. · 3.53 Impact Factor
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    ABSTRACT: Sickle cell anemia (SCA) is associated with a hypercoagulable state. Increased platelet activation is reported in SCA and SCA platelets may present augmented adhesion to the vascular endothelium, potentially contributing to the vaso-occlusive process. We sought to observe the effects of platelets (PLTs) from healthy control (CON) individuals and SCA individuals on endothelial activation, in vitro. Human umbilical vein endothelial cells (HUVEC) were cultured, in the presence, or not, of washed PLTs from CON or steady-state SCA individuals. Supernatants were reserved for cytokine quantification, and endothelial adhesion molecules (EAM) were analyzed by flow cytometry; gene expressions of ICAM1 and genes of the NF-κB pathway were analyzed by qPCR. SCA PLTs were found to be more inflammatory, displaying increased adhesive properties, an increased production of IL-1β and a tendency towards elevated expressions of P-selectin and activated αIIbβ3. Following culture in the presence of SCA PLTs, HUVEC presented significant augmentations in the expressions of the EAM, ICAM-1 and E-selectin, as well as increased IL-8 production and increased ICAM1 and NFKB1 (encodes p50 subunit of NF-κB) gene expressions. Interestingly, transwell inserts abolished the effects of SCA PLTs on EAM expression. Furthermore, an inhibitor of the NF-κB pathway, BAY 11-7082, also prevented the induction of EAM expression on the HUVEC surface by SCA PLTs. In conclusion, we find further evidence to indicate that platelets circulate in an activated state in sickle cell disease and are capable of stimulating endothelial cell activation. This effect appears to be mediated by direct contact, or even adhesion, between the platelets and endothelial cells and via NFκB-dependent signaling. As such, activated platelets in SCD may contribute to endothelial activation and, therefore, to the vaso-occlusive process. Results provide further evidence to support the use of anti-platelet approaches in association with other therapies for SCD.
    PLoS ONE 01/2014; 9(2):e89012. · 3.53 Impact Factor
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    ABSTRACT: BACKGROUND: Matching for Rh and K antigens has been used in an attempt to reduce antibody formation in patients receiving chronic transfusions but an extended phenotype matching including Fya and Jka antigens has also been recommended. The aim of this study was to identify an efficient transfusion protocol of genotype matching for patients with myelodysplastic syndrome (MDS) or chronic myelomonocytic leukaemia. We also examined a possible association of HLA class II alleles with red blood cell (RBC) alloimmunisation. MATERIALS AND METHODS: We evaluated 43 patients with MDS undergoing transfusion therapy with and without antibody formation. We investigated antigen-matched RBC units for ABO, D, C, c, E, e, K, Fya, Fyb, Jka, Jkb, S, s, Doa, Dob and Dia on the patients' samples and on the donor units serologically matched for them based on their ABO, Rh and K phenotypes and presence of antibodies. We also determined the frequencies of HLA-DRB1 alleles in the alloimmunised and non-alloimmunised patients. RESULTS: Seventeen of the 43 patients had discrepancies or mismatches for multiple antigens between their genotype-predicted profile and the antigen profile of the units of blood serologically matched for them. We verified that 36.8% of patients had more than one RBC alloantibody and 10.5% of patients had autoantibodies. Although we were able to find a better match for the patients in our extended genotyped/phenotyped units, we verified that matching for Rh and K would be sufficient for most of the patients. We also observed an over-representation of the HLA-DRB1*13 allele in the non-alloimmunised group of patients with MDS. DISCUSSION: In our population molecular matching for C, c, E, e, K was able to reduce RBC alloimmunisation in MDS patients. An association of HLA-DRB1*13 and protection from RBC alloimmunisation should be confirmed.
    Blood transfusion = Trasfusione del sangue 01/2014; · 1.86 Impact Factor
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    ABSTRACT: Stathmin 1 is an important cytoplasmic microtubule-destabilizing protein that plays critical roles in proliferation and accurate chromosome segregation through regulation of microtubule dynamics. High levels of Stathmin 1 expression have been reported in leukemia and solid tumors. However, Stathmin 1 has not been studied in myelodysplastic syndrome cells. We, herein, report that significantly higher Stathmin 1 levels were observed in proliferating hematopoietic cells, in high-risk MDS and acute leukemia cells. In addition, Stathmin 1 silencing in U937 and Namalwa leukemia cells reduced cell proliferation and clonogenicity. Our data suggest that Stathmin 1 expression may be related to the highly proliferative phenotype of hematopoietic cells and add new insights into the participation of Stathmin 1 in hematological malignancies.
    Leukemia research 12/2013; · 2.36 Impact Factor
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    ABSTRACT: Abstract Differential gene expression analysis by suppression subtractive hybridization with correlation to the metabolic pathways involved in chronic myeloid leukemia (CML) may provide a new insight into the pathogenesis of CML. Among the overexpressed genes found in CML at diagnosis are SEPT5, RUNX1, MIER1, KPNA6, and FLT3 while PAN3, TOB1 and ITCH were decreased when compared to healthy volunteers. Some genes were identified and involved in CML for the first time, including the TOB1which showed a low expression in CML patients during tyrosine kinase inhibitors treatment with no complete cytogenetic response. In agreement, reduced expression of TOB1 was also observed in resistant CML patients compared to responsive patients, this mightbe related to the deregulation of apoptosis and the signaling pathway leading to resistance. Most of identified genes were related to the regulation of NF-κB, AKT, Interferon and IL-4 in healthy cells. The results of this study combined with literature data showed specific gene pathways that might be explored as markers to assess the evolution and prognosis in CML as well as to identify new therapeutic targets.
    Leukemia & lymphoma 10/2013; · 2.61 Impact Factor
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    Clinics 10/2013; Clinics(68(10)):1371-1375.
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    ABSTRACT: The aim of this study was to evaluate the expression of protein tyrosine kinase 2 and protein tyrosine phosphatase non-receptor type 11, which respectively encode focal adhesion kinase protein and src homology 2 domain-containing protein-tyrosine phosphatase 2, in hematopoietic cells from patients with myelodysplastic syndromes. Protein tyrosine kinase 2 and tyrosine phosphatase non-receptor type 11 expressions were analyzed by quantitative polymerase chain reaction in bone marrow cells from patients with myelodysplastic syndromes and healthy donors. Protein tyrosine kinase 2 and tyrosine phosphatase non-receptor type 11 expressions did not significantly differ between normal cells and myelodysplastic cells. Our data suggest that despite the relevance of focal adhesion kinase and src homology 2 domain-containing protein-tyrosine phosphatase 2 in hematopoietic disorders, their mRNA expression do not significantly differ between total bone marrow cells from patients with myelodysplastic syndromes and healthy donors.
    Clinics (São Paulo, Brazil) 10/2013; 68(10):1371-5. · 1.59 Impact Factor
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    ABSTRACT: Intravascular hemolysis may have important pathophysiological consequences, such as the induction of cellular adhesion and vasculopathy. We compared the adhesive properties of red cells (RBC) and platelets in hereditary spherocytosis (HS), paroxysmal nocturnal hemoglobinuria (PNH) and sickle cell disease (SCD) patients. Design and Methods The adhesion of RBC and platelets, from patients and healthy subjects, was determined using static adhesion assays. RBC surface markers were characterized by flow cytometry and lactate dehydrogenase (LDH), plasma hemoglobin (pHb) and TNF-α were assayed in serum/plasma samples. pHb levels were elevated in all three hemolytic diseases, indicating the incidence of intravascular hemolysis. RBC adhesion and TNF-α were augmented in HS and SCD, but not in PNH. Reticulocyte counts were raised in the three diseases, but were higher in HS and SCD than in PNH; high expressions of CD71, CD36 and CD49d were observed on SCD RBC, while CD71 alone was increased on HS and PNH RBC. Splenectomy was associated with reversals of increased pHb, RBC adhesion, reticulocytes, RBC marker expression and inflammation in HS. In contrast, platelet adhesion was elevated in SCD and PNH, but not HS. Platelet adhesion correlated significantly with serum LDH, but not pHb, in the hemolytic disease cohort; interestingly, LDH did not correlate with reticulocytes or pHb levels. Results indicate that extravascular, rather than intravascular, hemolysis (and ensuing RBC production) may contribute to elevations in RBC adhesive properties in HS and SCD, while mechanisms peculiar to each disease may augment platelet adhesion in SCD and PNH.
    Clinical biochemistry 09/2013; · 2.02 Impact Factor
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    ABSTRACT: We hypothesized that specific molecular mutations are important biomarkers for response to DNA methyltransferase inhibitors (DNMT-inhibitors) and may have prognostic value in patients with myelodysplastic syndromes (MDS). Mutational analysis was performed in 92 patients with MDS and related disorders who received 5-azacytidine (n=55), decitabine (n=26) or both (n=11). Mutational status was correlated with overall response rate (ORR), progression free survival (PFS) and overall survival (OS) by univariate and multivariate analysis. Risk stratification models were created. TET2, DNMT3A, IDH1/IDH2, ASXL1, CBL, RAS, and SF3B1 mutations were found in 18%, 9%, 8%, 26%, 3%, 2%, and 13% of patients, respectively. In multivariate analysis, TET2(MUT) and/or DNMT3A(MUT) (P=.03), platelets≥100 × 10(9)/L (P=.007), and WBC<3.0 × 10(9)/L (P=0.03) were independent predictors of better response. TET2(MUT) and/or DNMT3A(MUT) (P=0.04) status was also independently prognostic for improved PFS, as were good or intermediate cytogenetic risk (P<0.0001), age<60 (P=0.0001), treatment with both 5-azacytidine and decitabine (P=0.02), and hemoglobin≥10 g/dl (P=0.01). Better OS was associated with ASXL1(WT) (P=0.008) and SF3B1(MUT) (P=0.01), and similar to PFS, cytogenetic risk (P=0.0002), age (P=0.02), and hemoglobin (P=0.04). These data support the role of molecular mutations as predictive biomarkers for response and survival in MDS patients treated with DNMT-inhibitors.Leukemia accepted article preview online, 18 September 2013. doi:10.1038/leu.2013.269.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 09/2013; · 10.16 Impact Factor
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    Atlas of Genetics and Cytogenetics in Oncology and Haematology. 09/2013; Atlas Genet Cytogenet Oncol Haematol(17 (9)):594-598.

Publication Stats

531 Citations
258.72 Total Impact Points

Institutions

  • 2013–2014
    • University of São Paulo
      San Paulo, São Paulo, Brazil
    • Universidade Federal de São Paulo
      San Paulo, São Paulo, Brazil
  • 2003–2014
    • University of Campinas
      • • Faculty of Medical Sciences
      • • Centro de Hematologia e Hemoterapia (HEMOCENTRO)
      Conceição de Campinas, São Paulo, Brazil