EDUARDO MAGALHAES REGO
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Clínica Médica, Faculdade de Medicina - Docente
LIM/31 - Laboratório de Genética e Hematologia Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/31 - Laboratório de Genética e Hematologia Molecular, Hospital das Clínicas, Faculdade de Medicina - Líder
93 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 93
- The PIP4K2 inhibitor THZ-P1-2 exhibits antileukemia activity by disruption of mitochondrial homeostasis and autophagy(2022) LIMA, Keli; PEREIRA-MARTINS, Diego Antonio; MIRANDA, Livia Bassani Lins de; COELHO-SILVA, Juan Luiz; LEANDRO, Giovana da Silva; WEINHAUSER, Isabel; CAVAGLIERI, Rita de Cassia; LEAL, Aline de Medeiros; SILVA, Wellington Fernandes da; LANGE, Ana Paula Alencar de Lima; VELLOSO, Elvira Deolinda Rodrigues Pereira; GRIESSINGER, Emmanuel; HILBERINK, Jacobien R.; AMMATUNA, Emanuele; HULS, Gerwin; SCHURINGA, Jan Jacob; REGO, Eduardo Magalhaes; MACHADO-NETO, Joao AgostinhoThe treatment of acute leukemia is challenging because of the genetic heterogeneity between and within patients. Leukemic stem cells (LSCs) are relatively drug-resistant and frequently relapse. Their plasticity and capacity to adapt to extracellular stress, in which mitochondrial metabolism and autophagy play important roles, further complicates treatment. Genetic models of phosphatidylinositol-5-phosphate 4-kinase type 2 protein (PIP4K2s) inhibition have demonstrated the relevance of these enzymes in mitochondrial homeostasis and autophagic flux. Here, we uncovered the cellular and molecular effects of THZ-P1-2, a pan-inhibitor of PIP4K2s, in acute leukemia cells. THZ-P1-2 reduced cell viability and induced DNA damage, apoptosis, loss of mitochondrial membrane potential, and the accumulation of acidic vesicular organelles. Protein expression analysis revealed that THZ-P1-2 impaired autophagic flux. In addition, THZ-P1-2 induced cell differentiation and showed synergistic effects with venetoclax. In primary leukemia cells, LC-MS/MS-based proteome analysis revealed that sensitivity to THZ-P1-2 is associated with mitochondrial metabolism, cell cycle, cell-of-origin (hematopoietic stem cell and myeloid progenitor), and the TP53 pathway. The minimal effects of THZ-P1-2 observed in healthy CD34(+) cells suggest a favorable therapeutic window. Our study provides insights into the pharmacological inhibition of PIP4K2s targeting mitochondrial homeostasis and autophagy, shedding light on a new class of drugs for acute leukemia.
- Patterns and Prognostic Impact of CNS Infiltration in Adults with Newly Diagnosed Acute Lymphoblastic Leukemia(2022) PERRUSO, Luiza Lapolla; VELLOSO, Elvira; ROCHA, Vanderson; REGO, Eduardo M.; SILVA, Wellington F.
- Phenformin increases early hematopoietic progenitors in the Jak2(V617F) murine model(2022) ALVES-SILVA, Antonio Bruno; FENERICH, Bruna Alves; FONSECA, Natasha Peixoto; FERNANDES, Jaqueline Cristina; COELHO-SILVA, Juan Luiz; PEREIRA-MARTINS, Diego Antonio; BIANCO, Thiago Mantello; SCHEUCHER, Priscila Santos; REGO, Eduardo Magalhaes; CHAHUD, Fernando; MACHADO-NETO, Joao Agostinho; FIGUEIREDO-PONTES, Lorena Lobo; TRAINA, FabiolaBackground. Myeloproliferative neoplasms (MPN) are disorders characterized by an alteration at the hematopoietic stem cell (HSC) level, where the JAK2 mutation is the most common genetic alteration found in classic MPN (polycythemia vera, essential thrombocythemia, and primary myelofibrosis). We and others previously demonstrated that metformin reduced splenomegaly and platelets counts in peripheral blood in JAK2(V617F) pre-clinical MPN models, which highlighted the antineoplastic potential of biguanides for MPN treatment. Phenformin is a biguanide that has been used to treat diabetes, but was withdrawn due to its potential to cause lactic acidosis in patients. Aims. We herein aimed to investigate the effects of phenformin in MPN disease burden and stem cell function in Jak2(V617F)-knockin MPN mice. Results. In vitro phenformin treatment reduced cell viability and increased apoptosis in SET2 JAK2(V67F) cells. Long-term treatment with 40 mg/kg phenformin in Jak2(V617F) knockin mice increased the frequency of LSK, myeloid progenitors (MP), and multipotent progenitors (MPP) in the bone marrow. Phenformin treatment did not affect peripheral blood counts, spleen weight, megakaryocyte count, erythroid precursors frequency, or ex vivo clonogenic capacity. Ex vivo treatment of bone marrow cells from Jak2(V617F) knockin mice with phenformin did not affect hematologic parameters or engraftment in recipient mice. Conclusions. Phenformin increased the percentages of LSK, MP, and MPP populations, but did not reduce disease burden in Jak2(V617F)-knockin mice. Additional studies are necessary to further understand the effects of phenformin on early hematopoietic progenitors.
- Differential cytotoxic activity of pharmacological inhibitors of IGF1R-related pathways in JAK2(V617F) driven cells(2022) FERNANDES, Jaqueline Cristina; FENERICH, Bruna Alves; ALVES-SILVA, Antonio Bruno; FONSECA, Natasha Peixoto; COELHO-SILVA, Juan Luiz; SCHEUCHER, Priscila Santos; REGO, Eduardo Magalhaes; FIGUEIREDO-PONTES, Lorena Lobo; MACHADO-NETO, Joao Agostinho; TRAINA, FabiolaMyeloproliferative neoplasms (MPN) belong to a group of clonal diseases of hematopoietic stem cells characterized by aberrant proliferation of mature myeloid lineages. The constitutive activation of the JAK2/STAT signaling pathway is now well established to play a central role in MPN pathogenesis; however, accumulating evidence now indicates that the IGF1R-mediated signaling pathway contributes to the maintenance of the malignant phenotype. Studies using inhibitors of IGF1-mediated signaling have reported cytotoxic effects in cellular and murine models of MPN, but no consensus has been reached regarding the potency and efficacy of inhibitors of the IGF1R-related pathway in this context. In the present study, we compared the potency and efficacy of three inhibitors of IGF1R-related pathways in a JAK2(V617F)-driven cellular model. These inhibitors (NT157, OSI-906, and NVP-AEW54) present antineoplastic activity with similar efficacy in Ba/F3 JAK2(V617F) cells, with NT157 showing the greatest potency. Both the induction of apoptosis and reduction in cell proliferation were associated with the observed reduction in cell viability. Downregulation of JAK2/STAT signaling was an advantageous off-target effect of all three inhibitors. These preclinical studies reinforce the potential of the IGF1R-related pathway as a therapeutic target in MPN.
article Acute promyelocytic leukaemia in lowincome and middle income countries: a Brazilian experience(2024) PEREIRA-MARTINS, Diego A.; WEINHAEUSER, Isabel; COELHO-SILVA, Juan L.; AMMATUNA, Emanuele; HULS, Geruin; SCHURINGA, Jan Jacob; REGO, Eduardo M.; LUCENA-ARAUJO, Antonio R.- M2 Macrophages Drive Resistance to Phagocytosis and Improve Mitochondrial Metabolism in Acute Myeloid Leukemia Facilitating Leukemic Transformation and In Vivo Engraftment(2022) WEINHAEUSER, Isabel; PEREIRA-MARTINS, Diego; ALMEIDA, Luciana Yamamoto de; HILBERINK, Jacobien R.; SILVEIRA, Douglas R. A.; QUEK, Lynn; ORTIZ, Cesar Alexander; LUCENA-ARAUJO, Antonio R.; VISSER, Nienke; AMMATUNA, Emanuele; HULS, Gerwin A.; REGO, Eduardo M.; SCHURINGA, Jan Jacob
- Challenges in Diagnosis and Treatment of Systemic Amyloidosis: 10 Years of Experience in a Public Brazilian University Center(2020) SZOR, Roberta Shcolnik; FERNANDES, Fabio; SEGURO, Fernanda S.; LINO, Angelina M.; JORGE, Lecticia B.; MENDONCA, Leonardo O.; FEITOSA, Valkercyo A.; CASTELLI, Jussara B.; REGO, Eduardo M.; JACOMASSI, Mayara; ALVES, Lucas B. O.; MARTINEZ, Gracia; ROCHA, Vanderson
- Toxicity Profile of PEG-Asparaginase in Adult Patients With Acute Lymphoblastic Leukemia in Brazil: A Multicenter Cross-Sectional Study(2020) SILVA, Wellington F. da; MASSAUT, Ires H. B.; BENDLIN, Rodrigo M.; ROSA, Lidiane I.; VELLOSO, Elvira D. R. P.; REGO, Eduardo M.; ROCHA, VandersonPegylated asparaginase was recently approved for use in Brazil. We reviewed its toxicity in adults with acute lymphoblastic leukemia. Fifty-seven patients were included, with remarkable thromboembolic (17%) and hepatic (77%) event rates. No fatal event was registered. Our incidence is similar to those reported in other trials. These effects should not preclude further use because most events are manageable. Background: Currently, pediatric-inspired regimens are commonly applied to adults with acute lymphoblastic leukemia (ALL) after the recent recognition that these protocols improve survival. While asparaginase in whatever available formulation is a key component of modern treatment of ALL, many adult oncologists and hematologists struggle to deal with its particular toxicities in clinical practice. We reviewed toxicity outcomes of pegylated asparaginase (PEG-ASP) in adults with ALL treated in 3 reference centers in Brazil. Patients and Methods: This was a cross-sectional retrospective chart-review study encompassing patients aged 15 years and older diagnosed with ALL or ambiguous-lineage leukemia who received at least one dose of PEG-ASP, regardless of the adopted regimen. Results: A total of 57 patients were included (age range, 15-57 years). Most patients (70%) received 2000 IU/m(2) as the initial dose, by intravenous route (72%). The incidence of thromboembolic events was 17.5%, and the main site was cerebral venous sinus (4/10). Thrombosis was more frequent in patients receiving second-line treatment. In obese patients, grade 3 hepatotoxicity and hyperbilirubinemia were more common. Clinical pancreatitis (grade 3 or higher) was found in 2 of 57 cases. PEG-ASP had to be discontinued in 19.3% of exposed patients (11/57). Conclusion: By reviewing the medical charts of adult patients with ALL from 3 reference centers, we found that our incidence of thrombotic and hepatic adverse events is similar to those reported in other trials involving PEG-ASP. Usually these effects should not preclude further use of the drug because most events are manageable in routine clinical practice.
- Novel inhibitor of hematopoietic cell kinase as a potential therapeutic agent for acute myeloid leukemia(2022) ROVERSI, Fernanda Marconi; BUENO, Maura Lima Pereira; SILVA, Juliete Aparecida Francisco da; ASSIS-MENDONCA, Guilherme Rossi; TORELLO, Cristiane Okuda; SHIRAISHI, Rodrigo Nato; PERICOLE, Fernando Viera; FERRO, Karla Priscila; DUARTE, Adriana Santos Silva; REGO, Eduardo Magalhaes; SAAD, Sara Teresinha OlallaMyelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are characterized by risk of relapses, poor survival, unwanted side effects and high toxicity with the current therapies. In light of these facts, there are efforts to develop new drugs specific for deregulated molecules that participate in leukemia pathogenesis. Hematopoietic cell kinase (HCK), an Src kinase family member, is overexpressed on hematopoietic stem cells of MDS and de novo AML patients and involved in the oncogenic process. Thus, we investigated in vitro, ex vivo and in vivo effects of a novel chemical compound targeting HCK inhibition (iHCK-37), in combination with the most used drugs for the treatment of MDS and de novo AML, 5-Azacytidine and Cytarabine. Herein, the combination treatment with iHCK-37 and 5-Azacytidine or Cytarabine demonstrated additive effects against leukemia cells, compared to either drug alone. iHCK-37 plus 5-Azacytidine or Cytarabine treatment was able to reduce the activation of oncogenic pathways, MAPK/ERK and PI3K/AKT, leading to reduction of ERK and AKT phosphorylation, and increased BAX and decreased BCL-XL protein expression. Moreover, treatment with iHCK-37 reduced MDS and AML CD34-positive cell numbers inside a 3D-structure but did not affect normal CD34-positive cell numbers. In vivo analysis showed that leukemic mice treated with iHCK-37 had reduced ERK and AKT proteins phosphorylation levels and leukocyte numbers. In conclusion, the iHCK-37 inhibitor has anti-neoplastic activity in leukemia cells without altering apoptosis and survival rate of normal cells, suggesting on-target malignant cell killing activity as a single agent or in combination with 5-Azacytidine or Cytarabine.
- Clinical Impact and Therapeutic Opportunity of Insulin Receptor Substrates 1/2 in Acute Myeloid Leukemia(2018) COELHO-SILVA, Juan Luiz; PEREIRA-MARTINS, Diego Antonio; SCHIAVINATO, Josiane Lilian; REGO, Eduardo Magalhaes; MACHADO-NETO, Joao Agostinho; TRAINA, Fabiola