Article
Hematology
Leonardo Luis Artico, Angelo Brunelli Albertoni Laranjeira, Livia Weijenborg Campos, Juliana Ronchi Correa, Priscila Pini Zenatti, Jose Barreto Campello Carvalheira, Sandra Regina Brambilla, Alexandre Eduardo Nowill, Silvia Regina Brandalise, Jose Andres Yunes
Summary: IGFBP7 plays an oncogenic role in acute lymphoblastic leukemia by promoting the perdurance of IGF1R at the cell surface, prolonging insulin/IGF stimulation. Clinical data suggest that IGFBP7 is a valid target for antibody-based therapeutic interventions in ALL.
Article
Oncology
Soyoung Park, Ali H. Abdel Sater, Johannes F. Fahrmann, Ehsan Irajizad, Yining Cai, Hiroyuki Katayama, Jody Vykoukal, Makoto Kobayashi, Jennifer B. Dennison, Guillermo Garcia-Manero, Charles G. Mullighan, Zhaohui Gu, Marina Konopleva, Samir Hanash
Summary: This study provides evidence for the overexpression of UHRF1 in acute lymphocytic leukemia (ALL) and reveals its direct interaction with c-Myc to regulate its expression, facilitating ALL cell growth through the cMYC-CDK4/6-phosphoRb signaling pathway. Analysis of human leukemia transcriptomic datasets shows concordant overexpression of UHRF1 in B-Cell and T-Cell ALL, suggesting its potential as a therapeutic target in ALL.
Article
Medicine, Research & Experimental
Violeta Garcia-Hernandez, David Arambilet, Yolanda Guillen, Teresa Lobo-Jarne, Maria Maqueda, Christos Gekas, Jessica Gonzalez, Arnau Iglesias, Nerea Vega-Garcia, Ines Sentis, Juan L. Trincado, Ian Marquez-Lopez, Holger Heyn, Mireia Camos, Lluis Espinosa, Anna Bigas
Summary: We investigated the role of beta-catenin/CTNNB1 in T-cell Acute Lymphoblastic Leukemia (T-ALL) patients and its involvement in therapy resistance. We identified a specific gene signature regulated by beta-catenin, TCF/LEF factors, and ZBTB33/Kaiso in T-ALL cell lines, which was highly represented in refractory T-ALL patients. We demonstrated the importance of beta-catenin in RNA and protein synthesis in T-ALL and proposed combination treatments involving beta-catenin inhibitors to enhance chemotherapy response and prevent disease relapse in T-ALL patients.
EMBO MOLECULAR MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
Ryosuke Wakabayashi, Yasunao Hattori, Shigekuni Hosogi, Yuki Toda, Kazuyuki Takata, Eishi Ashihara
Summary: Compound 31 was identified as an inhibitor of the Wnt/beta-catenin pathway, showing potential as a novel anti-AML agent by suppressing TCF activity, reducing AML cell proliferation, inducing apoptosis, and synergistically inhibiting cell growth when combined with idarubicin.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2021)
Article
Medicine, Research & Experimental
Filip Matthijssens, Nitesh D. Sharma, Monique Nysus, Christian K. Nickl, Huining Kang, Dominique R. Perez, Beatrice Lintermans, Wouter Van Loocke, Juliette Roels, Sofie Peirs, Lisa Demoen, Tim Pieters, Lindy Reunes, Tim Lammens, Barbara De Moerloose, Filip Van Nieuwerburgh, Dieter L. Deforce, Laurence C. Cheung, Rishi S. Kotecha, Martijn D. P. Risseeuw, Serge Van Calenbergh, Takeshi Takarada, Yukio Yoneda, Frederik W. van Delft, Richard B. Lock, Seth D. Merkley, Alexandre Chigaev, Larry A. Sklar, Charles G. Mullighan, Mignon L. Loh, Stuart S. Winter, Stephen P. Hunger, Steven Goossens, Eliseo F. Castillo, Wojciech Ornatowski, Pieter Van Vlierberghe, Ksenia Matlawska-Wasowska
Summary: The study demonstrates that the upregulation of RUNX2 acts as a dependency factor in high-risk subtypes of human T-ALL by regulating tumor metabolism and leukemic cell migration simultaneously.
JOURNAL OF CLINICAL INVESTIGATION
(2021)
Article
Multidisciplinary Sciences
Rashedul Islam, Catherine E. Jenkins, Qi Cao, Jasper Wong, Misha Bilenky, Annaick Carles, Michelle Moksa, Andrew P. Weng, Martin Hirst
Summary: Runt-related transcription factor 1 (RUNX1) is oncogenic in various leukemias and epithelial cancers, and its expression is associated with poor prognosis. It cooperates with other oncogenic factors to drive the expression of proto-oncogenes in T cell acute lymphoblastic leukemia (T-ALL), but the specific molecular mechanisms and cooperation with other factors are not well understood.
Article
Oncology
Mengping Xi, Shanshan Guo, Caicike Bayin, Lijun Peng, Florent Chuffart, Ekaterina Bourova-Flin, Sophie Rousseaux, Saadi Khochbin, Jian-Qing Mi, Jin Wang
Summary: This study found that the HDAC inhibitor chidamide has an anti-tumor effect on T-ALL cells, particularly by inhibiting the NOTCH1-MYC signaling axis. Clinical trial results support that chidamide treatment reduces minimal residual disease in patients and is well tolerated.
FRONTIERS OF MEDICINE
(2022)
Article
Multidisciplinary Sciences
Afonso R. M. Almeida, Joao L. Neto, Ana Cachucho, Mayara Euzebio, Xiangyu Meng, Rathana Kim, Marta B. Fernandes, Beatriz Raposo, Mariana L. Oliveira, Daniel Ribeiro, Rita Fragoso, Priscila P. Zenatti, Tiago Soares, Mafalda R. de Matos, Juliana Ronchi Correa, Mafalda Duque, Kathryn G. Roberts, Zhaohui Gu, Chunxu Qu, Clara Pereira, Susan Pyne, Nigel J. Pyne, Vasco M. Barreto, Isabelle Bernard-Pierrot, Emannuelle Clappier, Charles G. Mullighan, Ana R. Grosso, J. Andres Yunes, Joao T. Barata
Summary: The study shows that activating mutations in IL7Ra can initiate precursor B-cell acute lymphoblastic leukemia, and the mechanism is elucidated through research on a knock-in mouse model, providing new directions for the treatment of this type of leukemia.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Leonardo Luis Artico, Juliana Silveira Ruas, Jose Ricardo Teixeira Junior, Natacha Azussa Migita, Gustavo Seguchi, Xinghua Shi, Silvia Regina Brandalise, Roger Frigerio Castilho, Jose Andres Yunes
Summary: IGFBP7 promotes the permanence of IGF1R on the cell surface, prolonging Akt activation in the PI3K-Akt axis, which contributes to energy metabolism and glycolytic metabolism enhancement in BCP-ALL. Neutralizing IGFBP7 or inhibiting the PI3K-Akt pathway can restore the physiological levels of GLUT1 on the cell surface. This metabolic effect provides a mechanistic explanation for the negative impact of IGFBP7 knockdown or antibody neutralization on B cells in vitro and in vivo, highlighting its potential as a therapeutic target.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Oncology
Francesco Tamiro, Andrew P. Weng, Vincenzo Giambra
Summary: Leukemia-initiating cells (LIC) are unique cells in different types of leukemia that have self-renewing capabilities and produce tumors, which are functionally distinct from bulk leukemia cells. Current conventional treatments are not effective in eliminating LICs, hence innovative therapeutics targeting LICs hold promise for developing an effective cure for ALL.
Article
Oncology
Shi Hao Tan, Tze King Tan, Rui Yokomori, Minghui Liao, Xiao Zi Huang, Allen Eng Juh Yeoh, Takaomi Sanda
Summary: A hallmark of T-cell acute lymphoblastic leukemia (T-ALL) is the dysregulated expression of oncogenic transcription factors (TFs), including TAL1, NOTCH1 and MYC. In this study, researchers identified an enhancer element called enhMYCN that is aberrantly activated by the TAL1 complex in T-ALL cells. MYCN expression is required for the maintenance of TAL1-positive T-ALL cells, and inhibition of the mevalonate pathway, in which MYCN is involved, shows therapeutic potential for T-ALL.
Article
Oncology
Marissa Rashkovan, Robert Albero, Francesca Gianni, Pablo Perez-Duran, Hannah Miller, Adam L. Mackey, Elisabeth M. Paietta, Martin S. Tallman, Jacob M. Rowe, Mark R. Litzow, Peter H. Wiernik, Selina Luger, Maria Luisa Sulis, Rajesh K. Soni, Adolfo A. Ferrando
Summary: The early T-cell acute lymphoblastic leukemia (ETP-ALL) is genetically, immunophenotypically, and transcriptionally distinct from more mature T-cell acute lymphoblastic leukemia tumors. ETP-ALL exhibits specific metabolic circuitries involving increased biosynthesis of phospholipids and sphingolipids, and are specifically sensitive to the inhibition of the mevalonate pathway. Inhibition of cholesterol synthesis suppresses oncogenic AKT1 signaling and MYC expression, inhibiting the growth and survival of ETP-ALL cells.
Article
Oncology
Kimberly B. Johansson, Megan S. Zimmerman, Iryna V. Dmytrenko, Feng Gao, Daniel C. Link
Summary: The combination of idasanutlin and navitoclax shows high activity in T-ALL, inducing synergistic killing of cancer cells and increasing overall survival. This finding highlights the potential clinical significance of this combination therapy.
Article
Cell Biology
Xi Xu, Wenwen Zhang, Li Xuan, Yanhui Yu, Wen Zheng, Fang Tao, Jacqelyn Nemechek, Chong He, Weiwei Ma, Xue Han, Siyu Xie, Minyi Zhao, Jian Wang, Yuhua Qu, Qifa Liu, John M. Perry, Linjia Jiang, Meng Zhao
Summary: “T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy. In this study, a rare inhibitory receptor called programmed cell death 1 (PD-1) was identified as a marker for leukemia stem cells (LSCs) in T-ALL. Blocking PD-1 significantly eradicated LSCs and suppressed disease progression, and combination therapy with PD-1 blockade and chemotherapy extended survival. Mechanistically, PD-1+ LSCs had high NOTCH1-MYC activity and were protected against apoptosis. These findings provide a therapeutic approach for eliminating LSCs in T-ALL.”
NATURE CELL BIOLOGY
(2023)
Article
Hematology
Linlin Cao, Gustavo A. Ruiz Buendia, Nadine Fournier, Yuanlong Liu, Florence Armand, Romain Hamelin, Maria Pavlou, Freddy Radtke
Summary: Gain-of-function mutations in NOTCH1 are common in T-cell acute lymphoblastic leukemia (T-ALL) and targeting the Notch signaling pathway has shown promise for personalized medicine. Resistance to Notch inhibitors can occur due to mutational loss of PIK3R1, resulting in increased PI3K/AKT signaling. Combination therapy targeting CDK4/6 and NOTCH has been found to be the most effective in T-ALL xenotransplantation models.
Article
Oncology
Hisashi Takei, Juan Luiz Coelho-Silva, Cristina Tavares Leal, Adriana Queiroz Arantes Rocha, Thiago Mantello Bianco, Robert S. Welner, Yuta Mishima, Ikei S. Kobayashi, Ann Mullally, Keli Lima, Joao Agostinho Machado-Neto, Susumu S. Kobayashi, Lorena Lobo de Figueiredo-Pontes
Summary: Research suggests that targeting Bcl-xL, overexpressed in JAK2V617F-driven myeloproliferative neoplasms, may be a therapeutic option. Knockout of Bcl-xL can alleviate MPN-induced anemia and thrombocytopenia independently of JAK2 mutation status. Disruption of Bcl2 balance with obatoclax shows cytotoxicity in JAK2V617F cell models and reduces clonogenic capacity in bone marrow cells, offering a potential treatment option for controlling myeloid expansion in the disease.
Article
Public, Environmental & Occupational Health
Luigi Pisani, Anna Geke Algera, Ary Serpa Neto, Luciano Azevedo, Tai Pham, Frederique Paulus, Marcelo Gama de Abreu, Paolo Pelosi, Arjen M. Dondorp, Giacomo Bellani, John G. Laffey, Marcus J. Schultz
Summary: Despite similar disease severity and ventilation management, ICU mortality in patients without ARDS is higher in middle income countries (MICs) than in high-income countries (HICs), with a strong association with country-level economic status.
LANCET GLOBAL HEALTH
(2022)
Article
Microbiology
Emily S. Melzer, Takehiro Kado, Alam Garcia-Heredia, Kuldeepkumar Ramnaresh Gupta, Xavier Meniche, Yasu S. Morita, Christopher M. Sassetti, E. Hesper Rego, M. Sloan Siegrist
Summary: RodA and aPBPs are involved in polar peptidoglycan assembly and contribute to cell wall integrity maintenance in certain infection models, while RodA also enhances Mycobacterium smegmatis' resistance to cell wall damage.
JOURNAL OF BACTERIOLOGY
(2022)
Article
Hematology
Diego A. Pereira-Martins, Juan L. Coelho-Silva, Isabel Weinhauser, Pedro L. Franca-Neto, Douglas R. Silveira, Cesar Ortiz, Amanda Moreira-Aguiar, Marinus M. Lima, Luisa C. Koury, Raul A. de Melo, Ana B. Gloria, Evandro M. Fagundes, Bruno K. Lino, Katia Pagnano, Rosane Bittencourt, Elenaide Nunes, Fabiola Traina, Lorena Figueiredo-Pontes, Armand Keating, Martin S. Tallman, Raul C. Ribeiro, Richard Dilon, Arnold Ganser, Miguel A. Sanz, Nancy Berliner, Peter Valk, Bob Lowenberg, Tiziana Ottone, Nelida Noguera, Maria T. Voso, Francesca Paoloni, Paola Fazi, Emanuele Ammatuna, Gerwin Huls, Jan Jacob Schuringa, Eduardo M. Rego, Antonio R. Lucena-Araujo
Summary: A growing body of evidence indicates that higher-than-normal mitochondrial DNA content (mtDNAc) is associated with better prognosis in acute promyelocytic leukemia (APL) patients, regardless of tumor burden. This effect is more pronounced in low-risk patients. The multivariate Cox proportional hazard model reveals that high mtDNAc is independently associated with a decreased cumulative incidence of relapse. These findings highlight the potential role of mitochondrial metabolism in APL patients treated with ATRA.
BRITISH JOURNAL OF HAEMATOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Larissa Costa de Almeida, Felipe Antunes Calil, Natalia Cestari Moreno, Paula Rezende-Teixeira, Luiz Alberto Beraldo de Moraes, Paula Christine Jimenez, Carlos Frederico Martins Menck, Joao Agostinho Machado-Neto, Leticia Veras Costa-Lotufo
Summary: DNA-targeting agents have clinical significance in anticancer chemotherapy, but their widespread use is limited due to toxicity. This study used in silico modeling and transcriptomics to characterize the DNA repair pathways activated by pradimicin-IRD treatment. Pradimicin-IRD was found to be a DNA intercalating agent and can potentially inhibit DNA-binding proteins. Genes related to DNA repair functions were modulated by pradimicin-IRD, providing insights for further research on this compound as a new antineoplastic agent.
CHEMICO-BIOLOGICAL INTERACTIONS
(2023)
Article
Oncology
Keli Lima, Diego Antonio Pereira-Martins, Livia Bassani Lins de Miranda, Juan Luiz Coelho-Silva, Giovana da Silva Leandro, Isabel Weinhauser, Rita de Cassia Cavaglieri, Aline de Medeiros Leal, Wellington Fernandes da Silva, Ana Paula Alencar de Lima Lange, Elvira Deolinda Rodrigues Pereira Velloso, Emmanuel Griessinger, Jacobien R. Hilberink, Emanuele Ammatuna, Gerwin Huls, Jan Jacob Schuringa, Eduardo Magalhaes Rego, Joao Agostinho Machado-Neto
Summary: The treatment of acute leukemia is challenging due to genetic heterogeneity and drug resistance of leukemic stem cells (LSCs). A study found that the drug THZ-P1-2, which inhibits PIP4K2s, affects mitochondrial homeostasis and autophagy in acute leukemia cells, leading to apoptosis, DNA damage, and cell differentiation. It showed synergistic effects with venetoclax. Sensitivity to THZ-P1-2 was associated with mitochondrial metabolism, cell cycle, cell-of-origin, and the TP53 pathway in primary leukemia cells.
BLOOD CANCER JOURNAL
(2022)
Article
Immunology
Katharine Gurgel Dias Florencio, Evelline Araujo Edson, Keilla Santana da Silva Fernandes, Joao Paulo Mesquita Luiz, Francisco das Chagas Lima Pinto, Otilia Deusdenia Loiola Pessoa, Fernando de Queiroz Cunha, Joao Agostinho Machado-Neto, Diego Veras Wilke
Summary: Certain cytotoxic chemotherapics can activate the immune system through immunogenic cell death (ICD), leading to better and long-lasting antitumor responses. This study evaluated the ICD induction of four highly cytotoxic chromomycins A (CA(5-8)) in melanoma cells.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Oncology
Hugo Passos Vicari, Keli Lima, Leticia Veras Costa-Lotufo, Joao Agostinho Machado-Neto
Summary: This study demonstrates the potential efficacy of eribulin in hematologic cancers and identifies potential biomarkers of responsiveness. Eribulin shows selective effects on malignant blood cells and induces DNA damage and apoptosis markers. Combining eribulin with elacridar may overcome drug resistance in these diseases.
Article
Oncology
Cesar Alexander Ortiz Rojas, Abel Costa-Neto, Diego A. Pereira-Martins, Duy Minh Le, Dominique Sternadt, Isabel Weinhaeuser, Gerwin Huls, Jan Jacob Schuringa, Eduardo Magalhaes Rego
Summary: Acute myeloid leukemia (AML) is a blood cancer caused by genetic aberrations acquired by bone marrow progenitor cells, resulting in impaired hematopoiesis. Treatment options for AML are limited, with chemotherapy followed by hematopoietic stem cell transplant (HSCT) being the main approach. This study identified the ME1 gene as a biomarker of poor prognosis in AML patients undergoing HSCT, with ME1 expression being associated with energetic processes related to oxidative phosphorylation.
Article
Engineering, Multidisciplinary
Leonardo Raphael Zuardi, Cleide Lucia Araujo Silva, Eduardo Magalhaes Rego, Giovana Vacilotto Carneiro, Silvia Spriano, Antonio Nanci, Paulo Tambasco de Oliveira
Summary: In vitro study showed that titanium nanotopography modulates the osteogenic response and enhances the expression of alkaline phosphatase mRNA, activity, and osteopontin (OPN) levels. The presence of a blood clot tends to inhibit osteoblastic differentiation, but the coating of recombinant mouse (rm) BMP-7 on a nanostructured titanium surface promotes differentiation.
Article
Oncology
Keli Lima, Livia Bassani Lins de Miranda, Anali Del Milagro Bernabe Garnique, Bruna Oliveira de Almeida, Mariane Cristina do Nascimento, Guilherme Augusto Sousa Alcantara, Glaucia Maria Machado-Santelli, Eduardo Magalhaes Rego, Joao Agostinho Machado-Neto
Summary: AD80, a multikinase inhibitor, exhibits antineoplastic effects in pancreatic cancer cells by reducing cell viability and inducing mitotic aberrations, autophagy, and apoptosis. The drug also modulates several genes and signaling pathways, providing insights into potential therapeutic strategies for pancreatic cancer.
Article
Hematology
Andres Gomez-De Leon, Roberta Demichelis-Gomez, Abel da Costa-Neto, David Gomez-Almaguer, Eduardo Magalhaes Rego
Summary: The objective of this study is to review the current diagnostic and therapeutic landscape of AML in Latin America, reflecting the situation in other low- and middle-income countries and regions. Although most technologies and treatment options are available in the region, a significant proportion of patients have limited access to them. Mortality in the first weeks from diagnosis is higher in Latin America compared to developed countries.
Article
Biochemistry & Molecular Biology
Keli Lima, Maria Fernanda Lopes Carvalho, Diego Antonio Pereira-Martins, Frederico Lisboa Nogueira, Livia Bassani Lins de Miranda, Mariane Cristina do Nascimento, Rita de Cassia Cavaglieri, Jan Jacob Schuringa, Joao Agostinho Machado-Neto, Eduardo Magalhaes Rego
Summary: The study identified the correlation between the expression of phosphatidylinositol-5-phosphate 4-kinase type 2 (PIP4K2) and the response to antineoplastic agents in acute myeloid leukemia (AML). High levels of PIP4K2A were associated with resistance to venetoclax. The combination of THZ-P1-2 and venetoclax showed synergistic effects in AML cells and modulated multiple genes.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Letter
Oncology
Keli Lima, Hugo Passos Vicari, Jorge Antonio Elias Godoy Carlos, Jean Carlos Lipreri da Silva, Lorena Lobo de Figueiredo-Pontes, Eduardo Magalhaes Rego, Joao Agostinho Machado-Neto
HEMATOLOGY TRANSFUSION AND CELL THERAPY
(2022)