Priscila Santos Scheucher - Academia.edu (original) (raw)

Papers by Priscila Santos Scheucher

Investigational New Drugs, 2021

Stathmin 1 (STMN1) is a microtubule-destabilizing protein highly expressed in hematological malig... more Stathmin 1 (STMN1) is a microtubule-destabilizing protein highly expressed in hematological malignancies and involved in proliferation and differentiation. Although a previous study found that the PML–RARα fusion protein, which contributes to the pathophysiology of acute promyelocytic leukemia (APL), positively regulates STMN1 at the transcription and protein activity levels, little is known about the role of STMN1 in APL. In this study, we aimed to investigate the STMN1 expression levels and their associations with laboratory, clinical, and genomic data in APL patients. We also assessed the dynamics of STMN1 expression during myeloid cell differentiation and cell cycle progression, and the cellular effects of STMN1 silencing and pharmacological effects of microtubule-stabilizing drugs on APL cells. We found that STMN1 transcripts were significantly increased in samples from APL patients compared with those of healthy donors (all p < 0.05). However, this had no effect on clinical outcomes. STMN1 expression was associated with proliferation- and metabolism-related gene signatures in APL. Our data confirmed that STMN1 was highly expressed in early hematopoietic progenitors and reduced during cell differentiation, including the ATRA-induced granulocytic differentiation model. STMN1 phosphorylation was predominant in a pool of mitosis-enriched APL cells. In NB4 and NB4-R2 cells, STMN1 knockdown decreased autonomous cell growth (all p < 0.05) but did not impact ATRA-induced apoptosis and differentiation. Finally, treatment with paclitaxel (as a single agent or combined with ATRA) induced microtubule stabilization, resulting in mitotic catastrophe with repercussions for cell viability, even in ATRA-resistant APL cells. This study provides new insights into the STMN1 functions and microtubule dynamics in APL.

Blood, 2017

Introduction : Stathmin 1 is a microtubule destabilizer protein involved in the proliferation and... more Introduction : Stathmin 1 is a microtubule destabilizer protein involved in the proliferation and differentiation of early hematopoietic progenitors. Aberrant Stathmin 1 expression has been reported in hematological malignancies. Stathmin 1 silencing reduces cell proliferation and clonogenicity of leukemia cell lines. A previous study identified that the PML-RARα fusion protein, which is necessary to acute promyelocytic leukemia (APL) genesis, positively regulates Stathmin 1 at transcription and protein activity levels. However, Stathmin 1 expression and its impact on prognosis and leukemia cell biology have rarely been studied in APL. Objectives : To evaluate Stathmin 1 expression and its association with laboratory and clinical parameters in a cohort of APL patients. To investigate Stathmin 1 expression and activity upon all-trans retinoic acid (ATRA) treatment and during cell cycle in the PML-RARα cell lines. Finally, to phenocopy the effects of Stathmin 1 inhibition using the ph...

Hematology, Transfusion and Cell Therapy, 2021

Hematology, Transfusion and Cell Therapy, 2020

BMC Cancer, 2020

Background Differentiation syndrome (DS) is the main life-threatening adverse event that occurs i... more Background Differentiation syndrome (DS) is the main life-threatening adverse event that occurs in acute promyelocytic leukemia (APL) patients treated with all-trans retinoic acid (ATRA). Cytokine imbalances have been reported to play role during the developing of acute promyelocytic leukemia differentiation syndrome (APL-DS). However, the relationship between the plasma cytokine levels and their prognostic value for the prediction of DS developing in patients with APL during the treatment with ATRA and anthracyclines has not been previously reported. Methods In this study, we followed an APL cohort (n = 17) over 7 days of ATRA therapy in DS (n = 6) and non-DS groups (n = 11). Interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12p70 and TNF-α were measured in the peripheral blood plasma from 17 patients with APL and 11 healthy adult controls by using the cytometric bead array method. Results In non-DS patients, IL-8 plasma levels were significantly reduced in the seventh day of ATRA treatme...

Blood, 2005

Acute promyelocytic leukemia (APL) is associated with the t(15;17) which generates the PML-RARa f... more Acute promyelocytic leukemia (APL) is associated with the t(15;17) which generates the PML-RARa fusion gene. The encoded PML-RARα oncoprotein physically interacts with native PML impairing its function. PML is a potent inhibitor of proliferation and apoptosis. In addition, mouse embryonic fibroblasts in which PML was inactivated (PML−/− MEFs) exhibit a significant increase in the percentage (%) of cells in S phase accompanied by the decrease in the G0/G1 subpopulation. Transgenic mice (TM) hCG-PML-RARα develop a form of leukemia similar to human APL after a long period of latency, suggesting that PML-RARα expression is necessary but not sufficient to leukemogenesis. Leukemic cells of the TM model present increased proliferation associated with resistance of apoptosis. Nevertheless, it is not known whether these changes are present from birth and thus related to exclusively to PML/RARα expression, or appear late in life and are associated with additional mutagenic events. To address ...

Signal Transduction and Targeted Therapy, 2020

Recent data indicate that IGF1R/IRS signaling is a potential therapeutic target in BCR-ABL1-negat... more Recent data indicate that IGF1R/IRS signaling is a potential therapeutic target in BCR-ABL1-negative myeloproliferative neoplasms (MPN); in this pathway, IRS2 is involved in the malignant transformation induced by JAK2V617F, and upregulation of IGF1R signaling induces the MPN phenotype. NT157, a synthetic compound designed as an IGF1R-IRS1/2 inhibitor, has been shown to induce antineoplastic effects in solid tumors. Herein, we aimed to characterize the molecular and cellular effects of NT157 in JAK2V617F-positive MPN cell lines (HEL and SET2) and primary patient hematopoietic cells. In JAK2V617F cell lines, NT157 decreased cell viability, clonogenicity, and cell proliferation, resulting in increases in apoptosis and cell cycle arrest in the G2/M phase (p < 0.05). NT157 treatment inhibited IRS1/2, JAK2/STAT, and NFκB signaling, and it activated the AP-1 complex, downregulated four oncogenes (CCND1, MYB, WT1, and NFKB1), and upregulated three apoptotic-related genes (CDKN1A, FOS, a...

Blood, 2019

Background: The Jak2V617F mutation represents the most common molecular abnormality present in Ph... more Background: The Jak2V617F mutation represents the most common molecular abnormality present in Philadelphia chromosome-negative Classical Myeloproliferative Neoplasms (Ph-neg MPNs). The differential expression of genes/proteins between the hematopoietic stem cells (HSC) and the more committed bone marrow progenitors may reveal, at least in part, the contribution of each cell type to the pathogenesis of the disease. Recently, it has been shown that the deregulation of molecules of the BCL2 family in MPN increases the survival of the transformed hematopoietic stem and progenitor cells (HSPCs), which may contribute the progression of the disease (Figueiredo-Pontes et al, Blood #122:2852 2013). In this context, it is possible that the inhibition of Bcl-2 proteins may increase the sensibility of transformed HSPC to apoptosis leading to the control of myeloid proliferation and potential reduction of the Jak2 mutation allele burden. To date, the treatment of Ph-neg MPNs remains non-curativ...

Blood, 2011

1439 T-cell acute lymphoblastic leukemia (T-ALL) is a malignancy of immature T cells that account... more 1439 T-cell acute lymphoblastic leukemia (T-ALL) is a malignancy of immature T cells that accounts about 15% of pediatric and 25% of adult ALL cases. In the last years, several clinical and laboratory features have been described as prognostic markers; nevertheless, with intensification of therapy most of them have lost their predictive value. MicroRNA (miRNA) expression analysis has proved to be an useful tool for identifying specific subsets of cancer patients with relevant cytogenetic, laboratorial and clinical features. The aim of the present study was to determine if miRNAs may be useful markers in T-ALL. First, we performed a supervised analysis comparing the miRNA expression profile of T-ALL blasts from 36 T-ALL/CD56− and 12 T-ALL/CD56+. We selected CD56 as prognostic marker based on our previous report showing that the disease-free survival (DFS) of T-ALL/CD56+ patients was of 28.5 months compared to 69.8 in the CD56− group. Also patients tended to be older and to present no...

Blood, 2016

Background: Acute lymphoblastic leukemia (ALL) is an aggressive cancer of immature progenitors th... more Background: Acute lymphoblastic leukemia (ALL) is an aggressive cancer of immature progenitors that shows aberrant activation of signaling pathways. The IGF1/IGF1R signaling pathway is initiated through binding of the ligand (IGF1) to its transmembrane receptor (IGF1R), and subsequent activation of IRS1 and IRS2 proteins activating PI3K/Akt/mTOR and MAPK pathways, which are important signaling pathways reported to contributes to pathogenesis of ALL. However, the therapeutic potential of IGF1R/IRS signaling has not been previously studied in ALL cells. Aims: We herein aimed to investigate the effects of the pharmacological IGF1R/IR and IRS1/2 inhibition in ALL cells. Materials and Methods: T-ALL Jurkat and MOLT4, and B-ALL Namalwa and Raji cell lines were used. Peripheral blood or bone marrow mononuclear cells from ALL patients (T-ALL [n=2] and B-ALL [n=2]) at the time of diagnosis or relapse were used for functional studies and compared with health donors (n=2). Cell lines were trea...

Blood, 2010

3274 Propolis is a generic name for an adhesive resin collected, processed and used by bees to pl... more 3274 Propolis is a generic name for an adhesive resin collected, processed and used by bees to plug gaps, smooth internal walls and protect the entrance of the hive from intruders. Chemically is a complex blend of resin and fragments of plant tissues, volatile substances and wax. It contains over 300 constituents including benzoic acids, flavonoids and cinnamic acid derivatives. The Brazilian green propolis (BGP) has been shown to have immunomodulatory and antitumor properties in vitro and in vivo. We selected the caffeic acid phenethyl ester (CAPE), which is one of the components of BGP, as a candidate molecule for further studies regarding the antineoplastic activity. Cytotoxicity induced by Brazilian green propolis alcoholic extract (BGPAE) and CAPE in the cell lineages of acute promyelocytic leukemia (APL) (NB4 and NB4R2), and bone marrow cells from patients with acute myeloid leukemia (AML) at diagnosis (primary cells) was evaluated by annexin V/propidium iodide staining and an...

Blood, 2015

Natural killer (NK) cells are a subset of lymphocytes that play a critical role in both innate an... more Natural killer (NK) cells are a subset of lymphocytes that play a critical role in both innate and adaptive immune responses and provide defense against microbial infections and malignant transformation. When stimulated through their activating or cytokine receptors, NK cells rapidly produce cytokines and chemokines, including IFNγ, TNFα, TGFβ, GM-CSF, MIP1α, MIP1β, IL-10, and others, which can affect the function of hematopoietic stem cells (HSC)s. We hypothesized that NK-mediated cytokine production could regulate HSC function and that its deregulation may favor HSC malignant transformation and proliferation. In this regard, a few studies have shown that NK cells are defective in stem cell-derived diseases such as chronic myeloid leukemia (CML), for example, raising the hypothesis that immunological dysfunctions may be involved in initiating or contributing to the pathogenesis of myeloproliferative diseases. In contrast to CML, the role of NK cells in BCR-ABL1 negative-myeloprolif...

Blood, 2006

Acute promyelocytic leukemia (APL) is characterized by the infiltration of bone marrow (BM) and p... more Acute promyelocytic leukemia (APL) is characterized by the infiltration of bone marrow (BM) and peripheral blood (PB) by leukemic cells presenting a block of differentiation at the stage of promyelocytes. At the cytogenetic level, APL is associated with the t(15;17) which causes the fusion of two genes: Retinoic Receptor α (RARα) and Promyelocytic Leukemia (PML), on chromosomes 17 and 15, respectively. C/EBPα is a leucine zipper transcription factor essential to normal granulopoiesis. Mutations in C/EBPα gene are detected in 6–10% of Acute Myeloid Leukemia (AML) cases and C/EBPα activity is down-regulated by AML1-ETO fusion protein associated with FAB M2 subtype. We decided to test whether PML-RARα interferes with C/EBPα function, thus contributing to the blockage of differentiation characteristic of APL. We generated mutant mice expressing PML-RARα and haploinsufficient for C/EBPα (PR C/EBPα+/−) by crossing hCG PML-RARα transgenic mice (PR TM) and C/EBPα+/−. Leukemia was not detect...

Blood, 2014

Introduction: Lipid rafts are highly ordered membrane domains that are enriched in cholesterol an... more Introduction: Lipid rafts are highly ordered membrane domains that are enriched in cholesterol and sphingolipids and provide an environment for signal transduction proteins which control cell survival and cell death. Altered raft assembly has been implicated in cancer progression. Alkylphospholipids (APL) inhibit the AKT pathway and induce apoptosis of malignant cells but not of their normal counterparts when used at the same concentration. LAT2 (Linker for activation of T-cells family member 2) is a lipid raft component which is disrupted by APLs in leukemic cells. In the present study we evaluated the effect of perifosine, an APL with anticancer activity in humans, on the LAT2 and AKT pathways using a Mantle Cell Lymphoma (MCL) cell line (Granta-519 cells) as a model. We selected MCL cells to study because AKT is constitutively phosphorylated in this disease. Methods: We determined whether perifosine induced apoptosis of unmodified Granta-519 cells using flow cytometry, we measure...

Blood Advances, 2017

Despite the improved results achieved with dose-intense treatments, the prognosis of acute myeloi... more Despite the improved results achieved with dose-intense treatments, the prognosis of acute myeloid leukemia (AML) patients remains poor, with cure rates ranging from 60% to 70% in patients <60 years old, and overall cure rates of only 35% to 40%. Both disease-related genetic heterogeneity and

Clinical Cancer Research, 2018

Gefitinib and erlotinib are well-known epidermal growth factor receptor (EGFR) inhibitors approve... more Gefitinib and erlotinib are well-known epidermal growth factor receptor (EGFR) inhibitors approved by the Food and Drug Administration for the treatment of non-small cell lung cancer (NSCLC). Interestingly, patients with synchronous NSCLC and acute myeloid leukemia (AML) treated with erlotinib presented regression of both neoplasms, although AML myeloblasts were shown to lack expression of EGFR. In addition, preclinical studies have shown that gefitinib alone or combined with arsenic trioxide (ATO) or all-trans retinoic acid (ATRA) was able to induce differentiation in the EGFR-negative cell lines of acute promyelocytic leukemia (APL), which is a subtype of AML characterized by the t(15;17)/PML/RARA rearrangement. Our previous study demonstrated that EGFR gene expression levels were associated with prognostic outcomes of APL patients treated according to the International Consortium on APL protocol. However, the EGFR levels were not assessed at protein level. Two phase 3 trials repo...

Revista da Sociedade Brasileira de Medicina Tropical

Dengue virus (DENV) is the most important arthropod-borne viral disease worldwide with an estimat... more Dengue virus (DENV) is the most important arthropod-borne viral disease worldwide with an estimated 50 million infections occurring each year. In this study, we present a flow cytometry assay (FACS) for diagnosing DENV, and compare its results with those of the non-structural protein 1 (NS1) immunochromatographic assay and reverse transcriptase polymerase chain reaction (RT-PCR). All three assays identified 29.1% (39/134) of the patients as dengue-positive. The FACS approach and real-time RT-PCR detected the DENV in 39 and 44 samples, respectively. On the other hand, the immunochromatographic assay detected the NS1 protein in 40.1% (56/134) of the patients. The Cohen's kappa coefficient analysis revealed a substantial agreement among the three methods. The FACS approach may be a useful alternative for dengue diagnosis and can be implemented in public and private laboratories.

Revista Brasileira de Hematologia e Hemoterapia, 2017

Background: Evidence suggests that monoclonal B-cell lymphocytosis precedes all chronic lymphocyt... more Background: Evidence suggests that monoclonal B-cell lymphocytosis precedes all chronic lymphocytic leukemia cases, although the molecular mechanisms responsible for disease progression are not understood. Aberrant miRNA expression may contribute to the pathogenesis of chronic lymphocytic leukemia. The objective of this study was to compare miRNA expression profiles of patients with Binet A chronic lymphocytic leukemia with those of subjects with high-count monoclonal B-cell lymphocytosis and healthy volunteers (controls). Methods: Twenty-one chronic lymphocytic leukemia patients, 12 subjects with monoclonal B-cell lymphocytosis and ten healthy volunteers were enrolled in this study. Flow cytometry CD19 + CD5 +-based cell sorting was performed for the chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis groups and CD19 + cells were sorted to analyze the control group. The expressions of miRNAs (miR-15a, miR-16-1, miR-29b, miR-34a, miR-181a, miR-181b and miR-155) were determined by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Results: Significant differences between the expressions in the chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis groups were restricted to the expression of miR-155, which was higher in the former group. A comparison between healthy con

PLoS ONE, 2014

Telomere length measurement is an essential test for the diagnosis of telomeropathies, which are ... more Telomere length measurement is an essential test for the diagnosis of telomeropathies, which are caused by excessive telomere erosion. Commonly used methods are terminal restriction fragment (TRF) analysis by Southern blot, fluorescence in situ hybridization coupled with flow cytometry (flow-FISH), and quantitative PCR (qPCR). Although these methods have been used in the clinic, they have not been comprehensively compared. Here, we directly compared the performance of flow-FISH and qPCR to measure leukocytes' telomere length of healthy individuals and patients evaluated for telomeropathies, using TRF as standard. TRF and flow-FISH showed good agreement and correlation in the analysis of healthy subjects (R 2 = 0.60; p,0.0001) and patients (R 2 = 0.51; p,0.0001). In contrast, the comparison between TRF and qPCR yielded modest correlation for the analysis of samples of healthy individuals (R 2 = 0.35; p,0.0001) and low correlation for patients (R 2 = 0.20; p = 0.001); Bland-Altman analysis showed poor agreement between the two methods for both patients and controls. Quantitative PCR and flow-FISH modestly correlated in the analysis of healthy individuals (R 2 = 0.33; p,0.0001) and did not correlate in the comparison of patients' samples (R 2 = 0.1, p = 0.08). Intra-assay coefficient of variation (CV) was similar for flow-FISH (10.867.1%) and qPCR (9.567.4%; p = 0.35), but the inter-assay CV was lower for flow-FISH (9.667.6% vs. 16619.5%; p = 0.02). Bland-Altman analysis indicated that flow-FISH was more precise and reproducible than qPCR. Flow-FISH and qPCR were sensitive (both 100%) and specific (93% and 89%, respectively) to distinguish very short telomeres. However, qPCR sensitivity (40%) and specificity (63%) to detect telomeres below the tenth percentile were lower compared to flow-FISH (80% sensitivity and 85% specificity). In the clinical setting, flow-FISH was more accurate, reproducible, sensitive, and specific in the measurement of human leukocyte's telomere length in comparison to qPCR. In conclusion, flow-FISH appears to be a more appropriate method for diagnostic purposes.

Molecular & Cellular Proteomics, 2012