Article
Oncology
Hannah J. Uckelmann, Elena L. Haarer, Reina Takeda, Eric M. Wong, Charlie Hatton, Christian Marinaccio, Florian Perner, Masooma Rajput, Noa J. C. Antonissen, Yanhe Wen, Lu Yang, Lorenzo Brunetti, Chun -Wei Chen, Scott A. Armstrong
Summary: The dysregulation of developmental and stem cell-associated genes is a common phenomenon during cancer development. Most patients with acute myeloid leukemia (AML) express high levels of HOXA cluster genes and MEIS1, with an NPM1 mutation (NPM1c) being common in these cases. This study reveals that NPM1c directly binds to specific chromatin targets, collaborates with the MLL1 complex, and directly regulates oncogenic gene expression in AML.
Article
Biochemistry & Molecular Biology
Adam Folta, Marketa Sasinkova, Anna Durinikova, Marie Drncova, Barbora Weinbergerova, Jiri Mayer, Ivana Jeziskova
Summary: Researchers have developed a PCR method to simplify the preparation of NPM1 plasmid standards and accurately distinguish different NPM1 mutation plasmids. This method is faster, more convenient, and more cost-effective than traditional approaches.
MOLECULAR BIOLOGY REPORTS
(2022)
Review
Biochemistry & Molecular Biology
Ugo Testa, Elvira Pelosi, Germana Castelli
Summary: The current classification of acute myeloid leukemia (AML) relies on genomic alterations. AML with mutated nucleophosmin 1 (NPM1-mut) is the largest genetically defined group, accounting for about 30% of adult AMLs and is recognized as a distinct entity in the current AML classifications. NPM1-mut AML is usually associated with a normal karyotype and relatively favorable prognosis, but it is genetically, transcriptionally, and phenotypically heterogeneous. Recent studies highlight the need for additional stratification to improve therapeutic response for different subgroups of NPM1-mut AML patients.
Article
Hematology
Yun-Wei Zhang, Long Su, Ye-Hui Tan, Hai Lin, Xiao-Liang Liu, Qiu-Ju Liu, Jing-Nan Sun, Ming Zhang, Ya-Zhe Du, Fei Song, Wei Han, Su-Jun Gao
Summary: AML with NPM1 mutation is a distinct genetic entity with favorable outcomes. However, this study reveals that it is still a highly heterogeneous disorder. High NPM1 variant allele frequency (VAF) and certain co-mutated genes are associated with poorer outcomes. Additionally, measurable residual disease (MRD) after chemotherapy is an independent predictor. These findings are important for re-stratifying the prognoses of AML patients with NPM1 mutations.
ANNALS OF HEMATOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Sara La Manna, Daniele Florio, Concetta Di Natale, Fabiana Napolitano, Anna Maria Malfitano, Paolo A. Netti, Ilaria De Benedictis, Daniela Marasco
Summary: Protein association is a physiological process used by cells to regulate growth and adapt to stress conditions, including mutations. Mutations in the NPM1 protein can lead to the formation of amyloidogenic aggregates with fibrillar morphology, which could be harmful to cells. Analyzing the conformational characteristics of peptides with rare AML mutations of NPMc+ provides valuable insights into the structural consequences of cytoplasmic NPM1c+ mutations.
BIOORGANIC CHEMISTRY
(2021)
Article
Oncology
Xue Qing David Wang, Dandan Fan, Qinyu Han, Yiman Liu, Hongzhi Miao, Xinyu Wang, Qinglan Li, Dong Chen, Haley Gore, Pamela Himadewi, Gerd P. Pfeifer, Tomasz Cierpicki, Jolanta Grembecka, Jianzhong Su, Shasha Chong, Liling Wan, Xiaotian Zhang
Summary: Nucleophosmin (NPM1) is a nucleolar protein with various functions, and its mutation is commonly found in acute myeloid leukemia (AML). This study shows that mutant NPM1 directly binds to active chromatin regions and controls the transcription of AML-driving genes. These findings provide insights into the mechanism behind AML caused by NPM1 mutation and suggest potential therapeutic interventions.
Review
Biochemistry & Molecular Biology
Fabio Forghieri, Giovanni Riva, Ivana Lagreca, Patrizia Barozzi, Francesca Bettelli, Ambra Paolini, Vincenzo Nasillo, Beatrice Lusenti, Valeria Pioli, Davide Giusti, Andrea Gilioli, Corrado Colasante, Laura Galassi, Hillary Catellani, Francesca Donatelli, Annalisa Talami, Rossana Maffei, Silvia Martinelli, Leonardo Potenza, Roberto Marasca, Enrico Tagliafico, Rossella Manfredini, Tommaso Trenti, Patrizia Comoli, Mario Luppi
Summary: The C-terminal aminoacidic sequence from NPM1-mutated protein may serve as a leukemia-specific antigen, and different in silico instruments have identified the most immunogenic epitopes. Spontaneous development of endogenous NPM1-mutated-specific cytotoxic T cells has been observed in patients.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Oncology
Weijia Fu, Aijie Huang, Lili Xu, Yanni Peng, Lei Gao, Li Chen, Jie Chen, Gusheng Tang, Jianmin Yang, Xiong Ni
Summary: Cytogenetic abnormalities are significantly associated with a worse prognosis in NPM1(mut) acute myeloid leukemia (AML) patients, and patients who undergo alloHSCT have longer survival.
LEUKEMIA & LYMPHOMA
(2022)
Article
Oncology
Jan-Niklas Eckardt, Jan Moritz Middeke, Sebastian Riechert, Tim Schmittmann, Anas Shekh Sulaiman, Michael Kramer, Katja Sockel, Frank Kroschinsky, Ulrich Schuler, Johannes Schetelig, Christoph Roellig, Christian Thiede, Karsten Wendt, Martin Bornhaeuser
Summary: In this study, a multi-step deep learning approach was applied to automatically segment cells from bone marrow images, distinguish between AML samples and healthy controls with high accuracy, and predict the mutation status of NPM1. Unreported morphologic cell features were identified using occlusion sensitivity maps, enabling the DL model to provide accurate class predictions.
Review
Immunology
Justin Loke, Richard Buka, Charles Craddock
Summary: While most AML patients achieve complete remission with intensive chemotherapy, many face a risk of relapse if treated with chemotherapy alone. Allogeneic stem cell transplant has become a key treatment strategy for AML patients, especially for those in first complete remission and advanced stages. Despite a decrease in transplant-related mortality, there remains a need to address the risk of disease relapse.
FRONTIERS IN IMMUNOLOGY
(2021)
Review
Hematology
Brunangelo Falini
Summary: The importance and relevance of NPM1 mutations in AML, including their involvement in chromatin-level regulation and gene expression, as well as their implications for classification and potential targeted therapies.
AMERICAN JOURNAL OF HEMATOLOGY
(2023)
Article
Multidisciplinary Sciences
Brooks A. Benard, Logan B. Leak, Armon Azizi, Daniel Thomas, Andrew J. Gentles, Ravindra Majeti
Summary: This study aggregates multiple AML cohorts to explore the correlation between clonal abundance of somatic mutations and clinical outcomes. High variant allele frequency for certain mutations is associated with poor prognosis, while increased GATA2 variant allele frequency correlates with better outcomes. Clinical features such as white blood cell count and blast percentage are related to the subclonal abundance of mutations like TP53 and IDH1.
NATURE COMMUNICATIONS
(2021)
Article
Cell & Tissue Engineering
Rutvij A. Khanolkar, Rehan M. Faridi, Megan Kinzel, Kareem Jamani, Mary L. Savoie, Mona Shafey, Faisal M. Khan, Jan Storek
Summary: In cytogenetically intermediate-risk AML patients undergoing HCT, the presence of FLT3 and NPM1 mutations does not appear to have prognostic value in predicting outcomes.
Article
Oncology
Katerina Kuzelova, Barbora Brodska, Jana Markova, Martina Petrackova, Johannes Schetelig, Sarka Ransdorfova, Zdenka Gasova, Cyril Salek
Summary: The immune system plays a crucial role in eliminating residual leukemic cells during AML therapy. This study found that different immune markers are associated with AML genotypes. High levels of TIM-3 transcripts may serve as a marker for immune evasion in AML, and are also associated with lower survival rates.
Article
Hematology
Manuel J. Arana Rosainz, Nghia Nguyen, Amer Wahed, Laura C. Lelenwa, Nfn Aakash, Karen Schaefer, Adan Rios, Zeyad Kanaan, Lei Chen
Summary: This study investigated the clinicopathological and molecular features of NPM1-mutated AML with infrequent APL-like phenotype. It found an association between NPM1-mutated AML with TET2 or IDH2 co-mutations and APL-like immunophenotype. Additionally, significant elevated D-dimer levels or overt DIC at diagnosis could be relevant for this AML subtype.
INTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY
(2021)
Article
Cell & Tissue Engineering
Marie Sebert, Stephanie Gachet, Thierry Leblanc, Alix Rousseau, Olivier Bluteau, Rathana Kim, Raouf Ben Abdelali, Flore Sicre de Fontbrune, Loic Maillard, Carele Fedronie, Valentine Murigneux, Lea Bellenger, Naira Naouar, Samuel Quentin, Lucie Hernandez, Nadia Vasquez, Melanie Da Costa, Pedro H. Prata, Lise Larcher, Marie de Tersant, Matthieu Duchman, Anna Raimbault, Franck Trimoreau, Odile Fenneteau, Wendy Cuccuini, Nathalie Gachard, Nathalie Auger, Giulia Tueur, Maud Blanluet, Claude Gazin, Michele Souyri, Francina Langa Vives, Aaron Mendez-Bermudez, Helene Lapillonne, Etienne Lengline, Emmanuel Raffoux, Pierre Fenaux, Lionel Ades, Edouard Forcade, Charlotte Jubert, Carine Domenech, Marion Strullu, Benedicte Bruno, Nimrod Buchbinder, Caroline Thomas, Arnaud Petit, Guy Leverger, Gerard Michel, Marina Cavazzana, Eliane Gluckman, Yves Bertrand, Nicolas Boissel, Andre Baruchel, Jean-Hugues Dalle, Emmanuelle Clappier, Eric Gilson, Ludovic Deriano, Sylvie Chevret, Francois Sigaux, Gerard Socie, Dominique Stoppa-Lyonnet, Hugues de The, Christophe Antoniewski, Dominique Bluteau, Regis Peffault de Latour, Jean Soulier
Summary: Fanconi anemia (FA) patients with chromosome instability are prone to develop poor-prognosis myeloid leukemia. A longitudinal cohort study revealed a unique pattern of somatic structural variants and mutations in 62 patients with clonal evolution. The key driver of secondary leukemogenesis was identified as the early downregulation of basal p53 activation by MDM4, providing potential monitoring and therapeutic strategies.
Article
Oncology
Theodore W. Laetsch, Shannon L. Maude, Susana Rives, Hidefumi Hiramatsu., Henrique Bittencourt., Peter. Bader, Andre Baruchel, Michael Boyer, Barbara De Moerloose, Muna Qayed, Jochen Buechner, Michael A. Pulsipher, Gary Douglas Myers, Heather E. Stefanski, Paul L. Martin, Eneida Nemecek, Christina Peters, Gregory Yanik, Seong Lin Khaw, Kara L. Davis, Joerg Krueger, Adriana Balduzzi, Nicolas Boissel, Ranjan Tiwari, Darragh O'Donovan, Stephan A. Grupp
Summary: Clinical trials often have multiple endpoints with different maturity times. Clinical Trial Updates provide an opportunity to publish additional results beyond the initial report based on the primary endpoint. This update on the ELIANA trial demonstrates the long-term efficacy, safety, and quality of life improvements in pediatric and young adult patients with R/R B-ALL treated with tisagenlecleucel.
JOURNAL OF CLINICAL ONCOLOGY
(2023)
Letter
Biochemistry & Molecular Biology
Charlotte Smith, Aurore Touzart, Mathieu Simonin, Christine Tran-Quang, Guillaume Hypolite, Mehdi Latiri, Guillaume P. Andrieu, Estelle Balducci, Marie-emilie Dourthe, Ashish Goyal, Francoise Huguet, Arnaud Petit, Norbert Ifrah, Andre Baruchel, Herve Dombret, Elizabeth Macintyre, Christoph Plass, Jacques Ghysdael, Nicolas Boissel, Vahid Asnafi
Summary: The acquisition of genetic abnormalities leading to oncogene dysregulation is crucial for cancer development. In T-cell acute lymphoblastic leukemia (T-ALL) patients, the presence of 5'super-enhancer (5'SE) mutations in the TAL1 oncogene indicates a specific subgroup with poor prognosis, regardless of the level of oncogene dysregulation. Interestingly, targeting the MYB dependent oncogenic 5'SE using Mebendazole can induce MYB protein degradation and T-ALL cell death, showing efficacy in preclinical models. This study highlights the importance of understanding the mechanism of oncogene dysregulation for identifying clinically distinct patient subgroups and potential therapeutic targets.
Article
Oncology
Michael J. Dickinson, Pere Barba, Ulrich Jaeger, Nirav N. Shah, Didier Blaise, Javier Briones, Leyla Shune, Nicolas Boissel, Attilio Bondanza, Luisa Mariconti, Anne-Laure Marchal, David S. Quinn, Jennifer Yang, Andrew Price, Akash Sohoni, Louise M. Treanor, Elena J. Orlando, Jennifer Mataraza, Jaclyn Davis, Darlene Lu, Xu Zhu, Boris Engels, Laure Moutouh-de Parseval, Jennifer L. Brogdon, Michele Moschetta, Ian W. Flinn
Summary: CAR-T cell product quality and stemness are crucial for treatment efficacy. YTB323, a novel CAR-T cell therapy, showed enhanced in vivo expansion and antitumor activity at lower doses in preclinical and preliminary clinical trials. It also exhibited promising safety and clinical response rates, supporting its continued development for relapsed/refractory diffuse large B-cell lymphoma.
Article
Cell Biology
Anne-Charlotte Le Floch, Marie-Sarah Rouviere, Nassim Salem, Amira Ben Amara, Florence Orlanducci, Norbert Vey, Laurent Gorvel, Anne-Sophie Chretien, Daniel Olive
Summary: This study explored the impact of circulating ?d T-cell alterations on prognosis in newly diagnosed adult ALL patients. They found common alterations in CD8(+) T cells and ?d T cells of relapsed patients, including accumulation of early stage differentiation and increased expression of BTLA and CD73. The circulating ?d T-cell signature and Vd2 T-cell alterations were found to strongly discriminate patients by relapse status. These findings suggest the importance of Gd T cells, especially Vd2 T cells, in T-cell immunity and provide a rationale for further monitoring and enhancing Vd2 T cells in ALL.
Article
Multidisciplinary Sciences
Jeoffrey Pelletier, Marielle Balzano, Jerome Destin, Camille Montersino, Marjorie C. Delahaye, Tony Marchand, Anne-Laure Bailly, Florence Bardin, Emilie Coppin, Armelle Goubard, Remy Castellano, Marjolein J. W. de Bruijn, Jasper Rip, Yves Collette, Patrice Dubreuil, Karin Tarte, Cyril Broccardo, Rudi W. Hendriks, Claudine Schiff, Norbert Vey, Michel Aurrand-Lions, Stephane J. C. Mancini
Summary: B-cell acute lymphoblastic leukemia (B-ALL) is the malignant counterpart of developing B cells in the bone marrow (BM). Galectin-1 (GAL1) expressed in BM niches provides proliferation signals to normal pre-B cells through interaction with the pre-B cell receptor (pre-BCR). In murine and patient-derived xenograft (PDX) models, GAL1 produced by BM niches influences the development of pre-B ALL through pre-BCR-dependent signals, similar to normal pre-B cells. Targeting pre-BCR signaling in combination with cell-autonomous oncogenic pathways improves the treatment response in pre-B ALL PDX. Therefore, non-cell autonomous signals transmitted by BM niches could be potential targets to enhance B-ALL patient survival.
Editorial Material
Mycology
Colombe Saillard, Magali Bisbal, Morgan Avenin, Pierre Lehmann, Antoine Sannini, Laurent Chow-Chine, Luca Servan, Frederic Gonzalez, Evelyne d'Incan, Norbert Vey, Djamel Mokart
Article
Andrology
Virginie Barraud-Lange, Nicolas Boissel, Anne-Sophie Gille, Camille Jean, Leslie Sitbon, Benoit Schubert, Karima Yakouben, Mony Fahd, Matthieu Peycelon, Annabel Paye-Jaouen, Celine Chalas, Alexis Vanhaesebrouck, Francois Doz, Aurore Surun, Lauriane Lemelle, Sabine Sarnacki, Benedicte Neven, Pascale Philippe-Chomette, Christelle Dufour, Charlotte Rigaud, Guy Leverger, Marie-Dominique Tabone, Sabine Irtan, Corinne Pondaree, Harry Lezeau, Gilles Lenaour, Mathilde Sibony, Eva Comperat, Isabelle Brocheriou, Jean Philippe Wolf, Jean-Hugue Dalle, Catherine Poirot
Summary: This study reviewed 10 years of pediatric fertility preservation activity and found that the process is feasible, acceptable, safe, and potentially useful. The impact of chemotherapy on spermatogonia in testicular tissue was analyzed, and it was found that alkylating agents can reduce the chance of preserving spermatogonia.
Article
Oncology
E. Charton, C. Baldini, Y. Fayet, E. Schultz, L. Auroy, E. Vallier, A. Italiano, M. Robert, E. Coquan, N. Isambert, P. Moreau, C. Touzeau, C. Le Tourneau, Z. Ghrieb, J. J. Kiladjian, J. -P. Delord, C. Gomez Roca, N. Vey, F. Barlesi, T. Lesimple, N. Penel, J. -C. Soria, C. Massard, S. Besle
Summary: This study investigated the disparities in access to experimental treatment in early-phase clinical trials, revealing factors such as sex, care pathway, and geographic location as contributing factors. The findings of this study can help improve patient access to early-phase clinical trials.
Meeting Abstract
Oncology
Courtney D. DiNardo, Pau Montesinos, Lina Benajiba, Ana Triguero, Christian Recher, Andre C. Schuh, Mael Heiblig, Ashish Bajel, Arnaud Pigneux, Juan M. Alonso-Domiguez, Amir T. Fathi, Carolyn Grove, Hsin-An Hou, Michael Heuser, Sarit Assouline, Shaun Fleming, Dong-Yeop Shin, Kendra Sweet, Olatoyosi Odenike, Jessica Altman, Melissa Gaik Ming Ooi, Lao Zhentang, Nobert Vey, Joshua Zeidner, Amandeep Salhotra, Eunice Wang, Gary Schiller, Kimmo Porkka, Tsila Zuckerman, Violaine Havelange, Brian A. Jonas, Sujaatha Narayanan, Jun Ho Jang, Je-Hwan Lee, Anna M. Szpurka, Dana Heirich, Hsiao Rong Chen, Violet Hanft, Junjie Zhao, Ivelina Gueorguieva, Yin Zhang, Eytan M. Stein
Article
Hematology
Robin Noel, Christophe Zemmour, Catalina Montes de Oca, Nawel Belmecheri, Therese Aurran-Schleinitz, Diane Coso, Leonor Lopez Almeida, Lenaig Mescam, Norbert Vey, Jean Sebastien Blade, Borhane Slama, Reda Bouabdallah, Jean-Marc Schiano de Colella
Summary: This prospective phase 2 study aimed to evaluate the efficacy of Rituximab and Lenalidomide (R2) in Relapsed/Refractory Diffuse Large B Cell Lymphoma patients. However, the study failed to achieve its primary endpoint, indicating that R2 regimen is not recommended for patients with high-risk features.
Review
Oncology
Sylvain Garciaz, Thomas Miller, Yves Collette, Norbert Vey
Summary: The use of venetoclax, a BCL2 inhibitor, has revolutionized the treatment of AML patients who cannot undergo intensive chemotherapy. This drug triggers intrinsic apoptosis, showcasing how our understanding of molecular cell death pathways can be effectively applied in clinical settings. However, relapse is common among venetoclax-treated patients, suggesting the need to target additional regulated cell death pathways. This article reviews recognized regulated cell death pathways such as apoptosis, necroptosis, ferroptosis, and autophagy, and discusses the therapeutic opportunities and challenges in triggering regulated cell death in AML.
CANCER DRUG RESISTANCE
(2023)
Article
Hematology
Thomas Pabst, Cristina Papayannidis, Fatih Demirkan, Vadim Doronin, Laura M. Fogliatto, Christina Guttke, Emmanuel Gyan, Nada Hamad, Pilar Herrera, Anna Hultberg, Julie Jacobs, Amy J. Johnson, Angelique Langlois, Xuewen Ma, Giovanni Martinelli, Montserrat Arnan, Rouven Mueller, Kerri Nottage, Yishai Ofran, Muhit Ozcan, Olga Samoilova, Jaszianne A. Tolbert, Geralyn C. Trudel, Liang Xiu, Norbert Vey, Andrew Wei
Summary: This study aimed to determine the optimal dose of cusatuzumab in combination with azacitidine for the treatment of acute myeloid leukaemia. The results showed that cusatuzumab 20 mg/kg plus azacitidine was the optimal dose for further studies.
LANCET HAEMATOLOGY
(2023)
Meeting Abstract
Oncology
Yosr Hicheri, Cecile Castoldi, Raynier Devillier, Evelyne D'Incan, Sylvain Garciaz, Valerio Maisano, Colombe Saillard, Jerome Rey, Angela Granata, Samia Harbi, Faezeh Legrand, Sabine Furst, Didier Blaise, Norbert Vey
CLINICAL LYMPHOMA MYELOMA & LEUKEMIA
(2023)
Article
Oncology
Rathana Kim, Hugo Bergugnat, Lise Larcher, Matthieu Duchmann, Marie Passet, Stephanie Gachet, Wendy Cuccuini, Marina Lafage-Pochitaloff, Cedric Pastoret, Nathalie Grardel, Vahid Asnafi, Beat W. Schaefer, Eric Delabesse, Raphael Itzykson, Lionel Ades, Yosr Hicheri, Yves Chalandon, Carlos Graux, Patrice Chevallier, Mathilde Hunault, Thibaut Leguay, Francoise Huguet, Veronique Lheritier, Herve Dombret, Jean Soulier, Philippe Rousselot, Nicolas Boissel, Emmanuelle Clappier
Summary: Low hypodiploidy is a common subtype of B-cell acute lymphoblastic leukemia (B-ALL) in older adults, characterized by somatic TP53 biallelic alteration. The study reveals a link between aging and low hypodiploidy ALL, with TP53-mutant clonal hematopoiesis serving as a preleukemic reservoir that can give rise to aneuploidy and B-ALL.
BLOOD CANCER DISCOVERY
(2023)
