Article
Oncology
Brunangelo Falini, Sofia Sciabolacci, Lorenza Falini, Lorenzo Brunetti, Maria Paola Martelli
Summary: Mutations of Nucleophosmin (NPM1) are common in adult AML and are recognized as a distinct entity. Evaluation of NPM1 and FLT3 status is important for risk stratification and monitoring of MRD. Combining MRD monitoring with the ELN prognostication model can help guide therapeutic decisions for NPM1-mutated AML.
Article
Hematology
Sofia von Palffy, Hanna Thorsson, Pablo Pena-Martinez, Noelia Puente-Moncada, Carl Sanden, Anna M. Blom, Rasmus Henningsson, Gunnar Juliusson, Ben King, Niklas Landberg, Vladimir Lazarevic, Christina Orsmark-Pietras, Marianne Rissler, Vendela Rissler, Helena Agerstam, Marcus Jaras, Henrik Lilljebjorn, Thoas Fioretos
Summary: Mutations in the NPM1 gene are common in acute myeloid leukemia (AML), but relapse is still a significant concern. In this study, we identified the complement receptor C3AR as specifically expressed in NPM1-mutated AML cells, making it a potential target for antibody-based therapies. We also found that C3AR, in combination with GPR56, distinguishes leukemic stem cells from normal hematopoietic stem cells, and stimulation of C3AR-expressing cells leads to increased survival of AML cells. Furthermore, antibodies directed against C3AR effectively induce natural killer cell-mediated killing of primary AML cells, highlighting its potential as a therapeutic target in NPM1-mutated AML.
Review
Hematology
Brunangelo Falini, Lorenzo Brunetti, Maria Paola Martelli
Summary: Mutations of the nucleophosmin (NPM1) gene play a crucial role in adult acute myeloid leukemia (AML), with unique molecular, pathological, and clinical features. Accurate diagnosis and distinction of NPM1-mutated AML from other entities is important for guiding treatment decisions and assessing relapse risk. Monitoring measurable residual disease (MRD) using NPM1 mutations can provide valuable insights for therapeutic management after remission.
Article
Oncology
Vincenzo Maria Perriello, Ilaria Gionfriddo, Roberta Rossi, Francesca Milano, Federica Mezzasoma, Andrea Marra, Orietta Spinelli, Alessandro Rambaldi, Ombretta Annibali, Giuseppe Avvisati, Francesco Di Raimondo, Stefano Ascani, Brunangelo Falini, Maria Paola Martelli, Lorenzo Brunetti
Summary: One-third of adult AML patients have NPM1 mutations, with high expression of CD123 identified as a potential target for therapy in NPM1-mutated leukemic cells, particularly in CD34(+)CD38(-) cells. Targeting CD123 may be effective for treating NPM1-mutated AML, especially in combination with FLT3 mutations.
Review
Oncology
Rong Wang, Pan Xu, Lin-Lin Chang, Shi-Zhong Zhang, Hong-Hu Zhu
Summary: Acute myeloid leukemia (AML) is a heterogeneous disease characterized by the malignant proliferation of myeloid hematopoietic stem/progenitor cells. The NPM1 gene is the most frequently mutated gene in AML, found in approximately 30% of AML cases. While NPM1 is considered a good prognostic marker, some patients still relapse or fail to respond to treatment. Therefore, finding optimal therapies for AML with NPM1 mutations is urgently needed.
FRONTIERS IN ONCOLOGY
(2022)
Article
Hematology
Jad Othman, Manja Meggendorfer, Enrico Tiacci, Christian Thiede, Richard Schlenk, Richard Dillon, Sebastian Stasik, Alessandra Venanzi, Sarah Bertoli, Eric Delabesse, Pierre-Yves Dumas, Arnaud Pigneux, Audrey Bidet, Amanda F. Gilkes, Ian Thomas, Maria Teresa Voso, Alessandro Rambaldi, Lorenzo Brunetti, Vincenzo M. Perriello, Vibeke Andresen, Bjorn T. Gjertsen, Maria Paola Martelli, Christian Recher, Christoph Roellig, Martin Bornhaeuser, Hubert Serve, Carsten Mueller-Tidow, Claudia D. Baldus, Tortsten Haferlach, Nigel Russell, Brunangelo Falini
Summary: The characteristics of therapy-related NPM1-mutated AML (t-NPM1 AML) were found to be similar to de novo NPM1-mutated AML (dn-NPM1 AML) in terms of genetics, transcriptional profile, and clinical outcomes. However, t-NPM1 AML showed better overall survival and relapse-free survival compared to t-AML.
Review
Oncology
Tao-Chen He, Jian-Ang Li, Zhi-Hang Xu, Qiang-Da Chen, Han-Lin Yin, Ning Pu, Wen-Quan Wang, Liang Liu
Summary: In recent years, there has been a continuous increase in the incidence of cancer in young adults. Early-onset cancer (EOC), which refers to cancers diagnosed before the age of 50, represents a unique subgroup with distinct disease features. This review discusses several well-studied EOCs, highlighting their clinical and molecular similarities and differences. Understanding EOC as a distinct subtype compared to ordinary cancers is crucial for better prevention and treatment strategies.
CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Hanane Djamai, Jeannig Berrou, Melanie Dupont, Marie-Magdelaine Coude, Marc Delord, Emmanuelle Clappier, Alice Marceau-Renaut, Anna Kaci, Emmanuel Raffoux, Raphael Itzykson, Caroline Berthier, Hsin-Chieh Wu, Rita Hleihel, Ali Bazarbachi, Hugues de The, Andre Baruchel, Claude Gardin, Herve Dombret, Thorsten Braun
Summary: Studies have shown that BETi, like ATO + ATRA, induce differentiation and apoptosis in NPM1c AML cells independently of TP53; BETi induces differentiation through NPM1c degradation and maintains NPM1/BRD4 equilibrium in the nucleus; While ATO + ATRA demonstrates significant biological activity in NPM1c IMS-M2 cell line, those cells are resistant to BETi.
Article
Biochemistry & Molecular Biology
Anette Lodvir Hemsing, Kristin Paulsen Rye, Kimberley Joanne Hatfield, Hakon Reikvam
Summary: Targeted therapy with Rac1 inhibitors could effectively inhibit cell proliferation, induce apoptosis, and reduce cytokine levels in AML cells. AML patients with NPM1 mutations showed increased vulnerability to Rac1 inhibitors.
Review
Oncology
Roberta Ranieri, Giulia Pianigiani, Sofia Sciabolacci, Vincenzo Maria Perriello, Andrea Marra, Valeria Cardinali, Sara Pierangeli, Francesca Milano, Ilaria Gionfriddo, Lorenzo Brunetti, Maria Paola Martelli, Brunangelo Falini
Summary: NPM1 mutations are the most common genetic alteration in AML, and NPM1-mutated AML is regarded as a distinct genetic entity. This study provides an overview of potential targeted therapies against NPM1-mutated AML, including strategies to interfere with oligomerization and abnormal traffic of NPM1, induce protein degradation, and target nucleolar structure integrity. Therapeutic results with BCL-2 inhibitor and menin inhibitors, as well as immunotherapeutic approaches, are also discussed.
Article
Oncology
Anna Wojtuszkiewicz, Inge van der Werf, Stephan Hutter, Wencke Walter, Constance Baer, Wolfgang Kern, Jeroen J. W. M. Janssen, Gert J. Ossenkoppele, Claudia Haferlach, Jacqueline Cloos, Torsten Haferlach
Summary: This study explored differential splicing profiles associated with two common aberrations in AML, FLT3-ITD and NPM1 mutations. The co-occurrence of FLT3-ITD and mutated NPM1 was found to be associated with differential splicing of gene sets specific to FAB types, affecting cell cycle control and DNA damage response. Interestingly, differential expression mainly impacted genes involved in hematopoietic differentiation, indicating potential oncogenic relevance in FLT3-ITD+/NPM1+ samples.
Article
Oncology
Claudia Tregnago, Maddalena Benetton, Davide Padrin, Katia Polato, Giulia Borella, Ambra Da Ros, Anna Marchetti, Elena Porcu, Francesca Del Bufalo, Cristina Mecucci, Franco Locatelli, Martina Pigazzi
Summary: In this study, NPM1 mutations in AML were classified into A-like and non-A-like mutations based on the loss of tryptophan residues, revealing different biological features and sensitivity to chemotherapy. The differential expression of HOXA and HOXB genes and cell death pathways between these two types of mutations suggests the potential for further sub-classification and personalized management of NPM1-mutated AML patients.
Article
Hematology
Giulia Pianigiani, Andrea Gagliardi, Federica Mezzasoma, Francesca Rocchio, Valentina Tini, Barbara Bigerna, Paolo Sportoletti, Simona Caruso, Andrea Marra, Sara Peruzzi, Eleonora Petito, Giulio Spinozzi, Sharon Shacham, Yosef Landesman, Concetta Quintarelli, Paolo Gresele, Franco Locatelli, Lorenzo Brunetti, Maria Paola Martelli, Brunangelo Falini
Summary: NPM1 is the most frequently mutated gene in adults with acute myeloid leukemia (AML). The interaction between mutant NPM1 (NPM1c) and exportin-1 (XPO1) causes aberrant cytoplasmic dislocation of NPM1c and promotes high expression of homeobox (HOX) genes. However, the current dosing frequency and efficacy of drugs against NPM1-mutated AML are limited. The second-generation XPO1 inhibitor eltanexor, with a higher dosing frequency, can induce sustained downregulation of HOX genes, induce terminal AML differentiation, and prolong the survival of patients, providing important information for the design of clinical trials.
Article
Oncology
Ilaria Gionfriddo, Lorenzo Brunetti, Federica Mezzasoma, Francesca Milano, Valeria Cardinali, Roberta Ranieri, Alessandra Venanzi, Sara Pierangeli, Calogero Vetro, Giulio Spinozzi, Erica Dorillo, Hsin Chieh Wu, Caroline Berthier, Raffaella Ciurnelli, Melanie J. Griffin, Claire E. Jennings, Enrico Tiacci, Paolo Sportoletti, Franca Falzetti, Hugues de The, Gareth J. Veal, Maria Paola Martelli, Brunangelo Falini
Summary: Relapsed or refractory AML patients with NPM1 mutations face challenges in treatment, particularly in elderly and unfit individuals. Dactinomycin, a low-cost chemotherapeutic agent, shows potential as an alternative treatment option, possibly through its association with nucleolar stress. Further investigation in larger clinical studies is warranted.
Article
Oncology
Christopher P. Mill, Warren Fiskus, Kaberi Das, John A. Davis, Christine E. Birdwell, Tapan M. Kadia, Courtney D. DiNardo, Naval Daver, Koichi Takahashi, Koji Sasaki, Gerard M. McGeehan, Xinjia Ruan, Xiaoping Su, Sanam Loghavi, Hagop Kantarjian, Kapil N. Bhalla
Summary: Using CRISPR-Cas9 editing, it was found that knockout of mtNPM1 reduced sensitivity to Menin inhibitor and cytarabine, while knock-in of mtNPM1 enhanced sensitivity to these agents. Elderly AML patients with mtNPM1 and FLT3 co-mutations have poor outcomes and require new effective therapies. Pan-HDAC inhibitors and WEE1 tyrosine kinase inhibitor exhibited synergistic lethal activity with Menin inhibitor against mtNPM1 AML cells.
Article
Gastroenterology & Hepatology
Emily M. Heath, Richard B. Kim, Aze Wilson
Summary: This study found differences in healthcare outcomes, medication use, and treatment approaches between men and women with IBD, highlighting the importance of considering sex and gender factors when researching disease outcomes.
DIGESTIVE DISEASES AND SCIENCES
(2022)
Article
Oncology
Y. Wang, B. Acs, S. Robertson, B. Liu, L. Solorzano, C. Wahlby, J. Hartman, M. Rantalainen
Summary: The study developed a novel histological grade model (DeepGrade) based on digital whole-slide histopathology images and deep learning to improve risk stratification of NHG 2 breast cancer patients. DeepGrade provides independent prognostic information for stratification of NHG 2 cases and adds clinically relevant information over routine histological grading, serving as a cost-effective alternative to extract relevant information for clinical decisions.
ANNALS OF ONCOLOGY
(2022)
Article
Oncology
Safa Majeed, Mansi K. Aparnathi, Kevin C. J. Nixon, Vidhyasagar Venkatasubramanian, Fariha Rahman, Lifang Song, Jessica Weiss, Ranya Barayan, Vijithan Sugumar, Samir H. Barghout, Joel D. Pearson, Rod Bremner, Aaron D. Schimmer, Ming S. Tsao, Geoffrey Liu, Benjamin H. Lok
Summary: TAK-243 exhibits efficacy in preclinical models of small cell lung cancer (SCLC), with associations to various gene sets. TAK-243 synergizes with cisplatin/etoposide chemotherapy (C/E) and PARP inhibitor olaparib. TAK-243 is a potential therapeutic strategy to improve SCLC patient outcomes.
CLINICAL CANCER RESEARCH
(2022)
Article
Hematology
Lucas C. M. Arruda, Arwen Stikvoort, Melanie Lambert, Liqing Jin, Laura Sanchez Rivera, Renato M. P. Alves, Tales Rocha de Moura, Carsten Mim, Soren Lehmann, Rebecca Axelsson-Robertson, John E. Dick, Jonas Mattsson, Bjorn Onfelt, Mattias Carlsten, Michael Uhlin
Summary: A CD34-specific bi-specific T-cell engager (BTE) has been designed and tested in this study, demonstrating its ability to activate T cells and kill leukemia cells with the CD34(+) phenotype. In vivo experiments showed that the CD34-specific BTE had robust anti-tumor effects.
Article
Hematology
Stanley W. K. Ng, Tracy Murphy, Ian King, Tong Zhang, Michelle Mah, Zhibin Lu, Natalie Stickle, Narmin Ibrahimova, Andrea Arruda, Amanda Mitchell, Ming Mai, Rong He, Bindu Swapna Madala, David S. Viswanatha, John E. Dick, Steven Chan, Carl Virtanen, Mark D. Minden, Timothy Mercer, Tracy Stockley, Jean C. Y. Wang
Summary: The LSC17 gene expression score can predict survival outcomes and treatment response in AML patients, enabling personalized risk-adapted management.
Letter
Hematology
Baolin Tang, Jong Bok Lee, Siqi Cheng, Tianzhong Pan, Wen Yao, Dongyao Wang, Meijuan Tu, Zhiqiang Xiang, Xiandeng Chu, Liangquan Geng, Ping Qiang, Pingping Teng, Guangyu Sun, Huilan Liu, Jian Wang, Aaron D. Schimmer, Liming Yang, Zimin Sun, Li Zhang, Xiaoyu Zhu
AMERICAN JOURNAL OF HEMATOLOGY
(2022)
Article
Biochemical Research Methods
Philippe Weitz, Yinxi Wang, Kimmo Kartasalo, Lars Egevad, Johan Lindberg, Henrik Gronberg, Martin Eklund, Mattias Rantalainen
Summary: This study proposes a new approach to predict gene expression profiles based on the morphological features of tumors. By using convolutional neural networks, gene expression profiles were successfully predicted from hematoxylin and eosin-stained images, offering a cost-effective solution for large-scale research studies and molecular diagnostics.
Article
Oncology
Martine Dumont, Nana Weber-Lassalle, Charles Joly-Beauparlant, Corinna Ernst, Arnaud Droit, Bing-Jian Feng, Stephane Dubois, Annie-Claude Collin-Deschesnes, Penny Soucy, Maxime Vallee, Frederic Fournier, Audrey Lemacon, Muriel A. Adank, Jamie Allen, Janine Altmueller, Norbert Arnold, Margreet G. E. M. Ausems, Riccardo Berutti, Manjeet K. Bolla, Shelley Bull, Sara Carvalho, Sten Cornelissen, Michael R. Dufault, Alison M. Dunning, Christoph Engel, Andrea Gehrig, Willemina R. R. Geurts-Giele, Christian Gieger, Jessica Green, Karl Hackmann, Mohamed Helmy, Julia Hentschel, Frans B. L. Hogervorst, Antoinette Hollestelle, Maartje J. Hooning, Judit Horvath, M. Arf An Ikram, Silke Kaulfuss, Renske Keeman, Da Kuang, Craig Luccarini, Wolfgang Maier, John W. M. Martens, Dieter Niederacher, Peter Nurnberg, Claus-Eric Ott, Annette Peters, Paul D. P. Pharoah, Alfredo Ramirez, Juliane Ramser, Steffi Riedel-Heller, Gunnar Schmidt, Mitul Shah, Martin Scherer, Antje Stabler, Tim M. Strom, Christian Sutter, Holger Thiele, Christi J. van Asperen, Lizet van der Kolk, Rob B. van der Luijt, Alexander E. Volk, Michael Wagner, Quinten Waisfisz, Qin Wang, Shan Wang-Gohrke, Bernhard H. F. Weber, Peter Devilee, Sean Tavtigian, Gary D. Bader, Alfons Meindl, David E. Goldgar, Irene L. Andrulis, Rita K. Schmutzler, Douglas F. Easton, Marjanka K. Schmidt, Eric Hahnen, Jacques Simard
Summary: This study aimed to identify new genes associated with breast cancer risk through whole-exome sequencing. The results revealed 20 novel genes with evidence of association, but larger studies are needed for confirmation. Additionally, known genes such as BRCA1, BRCA2, PALB2, ATM, and CHEK2 were found to be associated with increased risk of breast cancer, although they only explain a fraction of the familial aggregation of the disease.
Article
Multidisciplinary Sciences
Bojing Liu, Yinxi Wang, Philippe Weitz, Johan Lindberg, Johan Hartman, Wanzhong Wang, Lars Egevad, Henrik Gronberg, Martin Eklund, Mattias Rantalainen
Summary: This study suggests that deep learning can detect potential prostate cancer in benign prostate biopsies, reducing false negatives and indicating men who could benefit from rebiopsies.
Article
Medicine, General & Internal
Lindsay A. Jibb, Stephanie M. Nanos, Sarah Alexander, Carmine Malfitano, Anne Rydall, Sumit Gupta, Aaron D. Schimmer, Camilla Zimmermann, Sarah Hales, Rinat Nissim, Charles Marmar, Katharina Schultebraucks, Kenneth Mah, Gary Rodin
Summary: This study aims to determine the prevalence, severity, longitudinal course, and predictors of traumatic stress symptoms in family caregivers of patients with acute leukemia and to understand their lived experience of traumatic stress and support needs.
Article
Neurosciences
Shraddha Pai, Shirley Hui, Philipp Weber, Soumil Narayan, Owen Whitley, Peipei Li, Viviane Labrie, Jan Baumbach, Anne L. Wheeler, Gary D. Bader
Summary: An open challenge in human genetics is to understand the impact of genotype variation on developmental cognition. In this study, the genetic underpinnings of cognitive tasks were analyzed in the Philadelphia Neurodevelopmental Cohort. A significant region of the Fibulin-1 gene was associated with nonverbal reasoning accuracy and white matter fractional anisotropy. This research advances the understanding of cognition and provides a framework for using systems-level data in biomedical domains.
Article
Oncology
Quang Thinh Trac, Yudi Pawitan, Tian Mou, Tom Erkers, Paivi Ostling, Anna Bohlin, Albin Osterroos, Mattias Vesterlund, Rozbeh Jafari, Ioannis Siavelis, Helena Backvall, Santeri Kiviluoto, Lukas M. Orre, Mattias Rantalainen, Janne Lehtio, Soren Lehmann, Olli Kallioniemi, Trung Nghia Vu
Summary: Despite the challenge of tumor heterogeneity, a robust prediction model called MDREAM has been developed and validated for predicting drug response in acute myeloid leukemia (AML) patients. This model integrates omics data, including mutations and gene expression, as well as large-scale drug testing. MDREAM achieved good predictive accuracy with a confidence score metric, and its web-based implementation is publicly available.
NPJ PRECISION ONCOLOGY
(2023)
Article
Biochemical Research Methods
Max Franz, Christian T. Lopes, Dylan Fong, Mike Kucera, Manfred Cheung, Metin Can Siper, Gerardo Huck, Yue Dong, Onur Sumer, Gary D. Bader
Summary: Cytoscape.js is an open-source graph library implemented in JavaScript. It can be used as a visualization software component to render interactive graphs in web browsers, or in a headless manner for server-side graph operations with Node.js.
Article
Immunology
Ioannis D. Dimitriou, David Meiri, Yulia Jitkova, Alisha R. Elford, Marianne Koritzinsky, Aaron D. Schimmer, Pamela S. Ohashi, Nahum Sonenberg, Robert Rottapel
Summary: In this study, the researchers found that 4E-BP1/2 proteins play a critical role in the proliferation of mouse CD8(+) T cells and the development of antiviral effector function. They also discovered that the translation of genes related to mitochondrial biogenesis is impaired in T cells derived from 4E-BP1/2-deficient mice.
JOURNAL OF IMMUNOLOGY
(2022)
Correction
Biochemistry & Molecular Biology
Qi Zhang, Bridget Riley-Gillis, Lina Han, Yannan Jia, Alessia Lodi, Haijiao Zhang, Saravanan Ganesan, Rongqing Pan, Sergej N. Konoplev, Shannon R. Sweeney, Jeremy A. Ryan, Yulia Jitkova, Kenneth Dunner, Shaun E. Grosskurth, Priyanka Vijay, Sujana Ghosh, Charles Lu, Wencai Ma, Stephen Kurtz, Vivian R. Ruvolo, Helen Ma, Connie C. Weng, Cassandra L. Ramage, Natalia Baran, Ce Shi, Tianyu Cai, Richard Eric Davis, Venkata L. Battula, Yingchang Mi, Jing Wang, Courtney D. DiNardo, Michael Andreeff, Jeffery W. Tyner, Aaron Schimmer, Anthony Letai, Rose Ann Padua, Carlos E. Bueso-Ramos, Stefano Tiziani, Joel Leverson, Relja Popovic, Marina Konopleva
SIGNAL TRANSDUCTION AND TARGETED THERAPY
(2022)