Article
Hematology
Andrea Biondi, Valentino Conter, Mammen Chandy, Primus Ewald, Marie Lucia de Martino Lee, Vivek S. Radhakrishnan, Wannaphorn Rotchanapanya, Patricia Scanlan, Owen Patrick Smith, Boubacar Togo, Peter Hokland
Summary: As hematologists, the best treatment for patients with blood diseases may vary due to differing opinions and constraints, as well as differences in patient presentation and understanding worldwide. Patients in developed countries often present early and have a better understanding of their disease, impacting treatment management and outcomes.
BRITISH JOURNAL OF HAEMATOLOGY
(2022)
Article
Multidisciplinary Sciences
Yin-Chen Hsu, Chih-Hsiang Yu, Yan-Ming Chen, Kathryn G. Roberts, Yu-Ling Ni, Kai-Hsin Lin, Shiann-Tarng Jou, Meng-Yao Lu, Shu-Huey Chen, Kang-Hsi Wu, Hsiu-Hao Chang, Dong-Tsamn Lin, Shu-Wha Lin, Ze-Shiang Lin, Wei-Tzu Chiu, Chia-Ching Chang, Bing-Ching Ho, Charles G. Mullighan, Sung-Liang Yu, Yung-Li Yang
Summary: Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukaemia (ALL) is a high-risk subtype with genomic alterations that activate cytokine receptor and kinase signalling. Patients with non-Ph kinase fusions have inferior outcomes compared to those with other common genetic alterations. The prevalence of non-Ph kinase fusions in Taiwanese cohort was lower than in Caucasian populations, suggesting potential implications for future clinical trials with tyrosine kinase inhibitors in Taiwan.
SCIENTIFIC REPORTS
(2021)
Article
Oncology
Liwen Zhu, Xinyu Li, Diandian Liu, Wenke Bai, Huaqing Yang, Qianyi Cheng, Luhong Xu, Jianpei Fang
Summary: This study uncovered a reciprocal loop of MAD2L1/TYK2/STAT3, which contributed to the development of B-ALL. Therefore, MAD2L1 can be considered a potential diagnostic biomarker as well as a novel therapeutic target for B-ALL.
JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY
(2023)
Article
Oncology
Ioannis Peppas, Anthony M. Ford, Caroline L. Furness, Mel F. Greaves
Summary: Children with newly diagnosed acute lymphoblastic leukaemia may have a delayed maturation of the gut microbiome compared with healthy children, which could be associated with early-life epidemiological factors and contribute to the risk of transformation of preleukaemic clones in response to common infectious triggers.
NATURE REVIEWS CANCER
(2023)
Review
Pediatrics
Adriana Balduzzi, Jochen Buechner, Marianne Ifversen, Jean-Hugues Dalle, Anca M. Colita, Marc Bierings
Summary: This review explores the best treatment options and new developments in hematopoietic stem cell transplantation for children under the age of four with acute lymphoblastic leukemia.
FRONTIERS IN PEDIATRICS
(2022)
Article
Oncology
Ashlee J. Thomson, Jacqueline A. Rehn, Susan L. Heatley, Laura N. Eadie, Elyse C. Page, Caitlin Schutz, Barbara J. Mcclure, Rosemary Sutton, Luciano Dalla-Pozza, Andrew S. Moore, Matthew Greenwood, Rishi S. Kotecha, Chun Y. Fong, Agnes S. M. Yong, David T. Yeung, James Breen, Deborah L. White
Summary: This study optimized the workflow for gene fusion detection, especially in the detection of Immunoglobulin Heavy Chain gene fusions. By adjusting the filtering steps, the sensitivity and reporting rate for this type of fusion were improved. The study provides alternative detection methods for difficult-to-detect high-risk B-ALL subtypes.
Review
Health Care Sciences & Services
Ross Salvaris, Pasquale Luke Fedele
Summary: In the past decade, significant progress has been made in understanding the genetic mutations underlying acute lymphoblastic leukemia (ALL), leading to the discovery of driver mutations with prognostic implications. Targeted therapies and immunotherapies have shown promise in treating different subtypes of ALL, but come with unique toxicities and sequencing considerations. Advances in T-ALL have been slower compared to B-ALL, but promising results have been seen with agents targeting T cell antigens like nelarabine and CAR T cell therapy.
JOURNAL OF PERSONALIZED MEDICINE
(2021)
Article
Pathology
Artturi Makinen, Atte Nikkila, Juha Mehtonen, Susanna Teppo, Laura Oksa, Jessica Nordlund, Samuli Rounioja, Virva Pohjolainen, Saara Laukkanen, Merja Heinaniemi, Timo Paavonen, Olli Lohi
Summary: B-cell lineage acute lymphoblastic leukaemia (B-ALL) is the most common paediatric malignancy. The expression of BCL6 protein is associated with prognosis, but the expression varies among different subtypes, requiring careful evaluation combining protein and genetic/transcriptomic data.
Review
Biochemistry & Molecular Biology
Erica Dander, Chiara Palmi, Giovanna D'Amico, Giovanni Cazzaniga
Summary: Genetic lesions predisposing to pediatric B-ALL can lead to a clinically silent pre-leukemic phase. Inflammation in the microenvironment is crucial for promoting genetic instability and disease manifestation. Interaction between leukemic cells and the surrounding microenvironment influences leukemia development, chemoresistance, and other properties, highlighting the importance of a dual targeting therapeutic strategy.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Anna Mroczek, Joanna Zawitkowska, Jerzy Kowalczyk, Monika Lejman
Summary: Acute lymphoblastic leukaemia (ALL) is a common childhood cancer with a cure rate of over 80%, diagnosed based on various features. Despite unclear pathogenesis, research focuses on new therapeutic targets and predictive factors for improved patient outcomes.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Mathematics, Applied
Odelaisy Leon-Triana, Soukaina Sabir, Gabriel F. Calvo, Juan Belmonte-Beitia, Salvador Chulian, Alvaro Martinez-Rubio, Maria Rosa, Antonio Perez-Martinez, Manuel Ramirez-Orellana, Victor M. Perez-Garcia
Summary: Immunotherapies, particularly the use of CAR T cells to treat B-cell malignancies, have shown significant success in targeting cancer cells. A mathematical model describing the time response of leukaemias to CAR T cell injection accounts for various biological processes and predicts the dynamics of different compartments post-injection, emphasizing the potential role of competition between leukaemic and CAR T cells in cancer relapses.
COMMUNICATIONS IN NONLINEAR SCIENCE AND NUMERICAL SIMULATION
(2021)
Review
Medicine, General & Internal
Wei Sun, Xiaojun Huang
Summary: Allogeneic hematopoietic stem cell transplantation is the standard treatment for adult acute lymphoblastic leukemia, and the development of immunotherapy has expanded treatment options for relapsed or refractory ALL patients.
CHINESE MEDICAL JOURNAL
(2022)
Review
Oncology
Zhilian Jia, Zhaohui Gu
Summary: PAX5 is a key regulator of B-cell development and maintenance, and is frequently targeted by genetic alterations in B-cell acute lymphoblastic leukemia (B-ALL). These alterations can result in the blockage of B-cell development and malignant transformation of normal B cells, with different functional impacts and distribution patterns. Recent studies have identified PAX5 genetic lesions as initiating or driver events in B-ALL, and potential therapeutic targets for certain cases.
FRONTIERS IN ONCOLOGY
(2022)
Review
Pediatrics
Jochen Buechner, Ignazio Caruana, Annette Kuenkele, Susana Rives, Kim Vettenranta, Peter Bader, Christina Peters, Andre Baruchel, Friso G. Calkoen
Summary: Chimeric antigen receptor T-cell therapy (CAR-T) targeting CD19 has shown significant efficacy in treating paediatric patients and adolescents and young adults with relapsed/refractory B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). Tisagenlecleucel, the first approved CD19 CAR-T, has become a viable treatment option for patients who repeatedly relapse or fail after haematopoietic stem cell transplantation (HSCT). However, a proportion of patients still experience disease relapse after CAR-T treatment, leading to the proposal of consolidative HSCT. Despite this, research is ongoing to investigate CAR-T as a potential substitute for HSCT in order to reduce treatment-related mortality and late effects.
FRONTIERS IN PEDIATRICS
(2022)
Review
Hematology
Rachael Pocock, Nadine Farah, Simon E. Richardson, Marc R. Mansour
Summary: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of T-cell progenitors that remains challenging to treat despite improvements in survival outcomes over the past 50 years. Relapsed and refractory cases are particularly difficult to manage, and T-ALL is proving to be a more challenging immunotherapeutic target compared to B-ALL. Understanding the basic biology of T-ALL is crucial in repurposing established treatments and developing novel therapeutic approaches.
BRITISH JOURNAL OF HAEMATOLOGY
(2021)
Article
Hematology
Yuzhe Shi, Melanie C. Beckett, Helen J. Blair, Ricky Tirtakusuma, Sirintra Nakjang, Amir Enshaei, Christina Halsey, Josef Vormoor, Olaf Heidenreich, Anja Krippner-Heidenreich, Frederik W. van Delft
Summary: The study identified the critical role of LCK in T-cell acute lymphoblastic leukemia (T-ALL) cell proliferation, with combination therapy of LCK inhibition with dasatinib (DAS) leading to cell death, which was enhanced by dexamethasone (DEX). These findings provide a strategy to improve the efficacy of current chemotherapy and overcome glucocorticoid resistance in high-risk T-ALL patients.
Article
Oncology
Laura Godfrey, Nicholas T. Crump, Sorcha O'Byrne, I-Jun Lau, Siobhan Rice, Joe R. Harman, Thomas Jackson, Natalina Elliott, Gemma Buck, Christopher Connor, Ross Thorne, David J. H. F. Knapp, Olaf Heidenreich, Paresh Vyas, Pablo Menendez, Sarah Inglott, Philip Ancliff, Huimin Geng, Irene Roberts, Anindita Roy, Thomas A. Milne
Summary: MLL gene rearrangements are a common cause of aggressive and incurable acute lymphoblastic leukemias in infants and children, with the most common MLLr producing an MLL-AF4 fusion protein that promotes leukemogenesis by activating key target genes. The aberrant expression of PROM1/CD133 is essential for leukemic cell growth, mediated by direct binding of MLL-AF4 and controlled by an intragenic H3K79me2/3 enhancer element. The dual locus regulation between PROM1 and the nearby gene TAPT1 is reflected in a strong correlation of expression in leukemia.
Article
Multidisciplinary Sciences
Rinako Nakagawa, Amparo Toboso-Navasa, Marta Schips, George Young, Leena Bhaw-Rosun, Miriam Llorian-Sopena, Probir Chakravarty, Abdul Karim Sesay, George Kassiotis, Michael Meyer-Hermann, Dinis Pedro Calado
Summary: Affinity maturation in germinal centers depends on efficient positive selection of B cells in the light zone. Different subpopulations of cMyc(+) GC B cells are identified and characterized, with higher-affinity cells diverging towards plasmablasts and lower-affinity cells towards memory B cell precursors. This dynamic process of positive selection leads to the generation of three distinct B cell fates, ensuring clonal diversity for broad protection.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Medicine, Research & Experimental
Elizabeth A. Kuczynski, Giulia Morlino, Alison Peter, Anna M. L. Coenen-Stass, Jennifer Moss, Neha Wali, Oona Delpuech, Avinash Reddy, Anisha Solanki, Charles Sinclair, Dinis P. Calado, Larissa S. Carnevalli
Summary: This study established a novel mouse model of PTCL by transplanting lymphoma cells into immune-competent mice, which exhibited similar B-cell activation and lymphomagenesis as observed in human PTCL. Molecular profiling identified specific gene expressions and mutations related to high-risk PTCL subtype. Targeting the DNA damage response pathway led to prolonged treatment responses in vivo, suggesting the potential of DDR inhibition as an effective therapy for PTCL.
EMBO MOLECULAR MEDICINE
(2022)
Review
Oncology
Erica Brivio, Andre Baruchel, Auke Beishuizen, Jean-Pierre Bourquin, Patrick A. Brown, Todd Cooper, Lia Gore, E. Anders Kolb, Franco Locatelli, Shannon L. Maude, Francis J. Mussai, Britta Vormoor-Burger, Josef Vormoor, Arend von Stackelberg, C. Michel Zwaan
Summary: Despite improvements in treating newly diagnosed leukaemia and lymphoma in children, refractory or relapsed cases remain difficult to manage. Novel agents that offer less toxicity while maintaining efficacy are being explored. However, drug development for paediatric cancers lags behind adult therapeutic options.
EUROPEAN JOURNAL OF CANCER
(2022)
Article
Medicine, General & Internal
Tobias Menne, Daniel Slade, Joshua Savage, Sarah Johnson, Julie Irving, Pamela Kearns, Ruth Plummer, Geoff Shenton, Gareth J. Veal, Britta Vormoor, Josef Vormoor, Lucinda Billingham
Summary: The study aims to evaluate the combination of selumetinib and dexamethasone in adult and paediatric patients with relapsed/refractory RAS pathway mutant ALL. The research will be conducted in multiple countries and results will be disseminated through national and international conferences and peer-reviewed publications.
Review
Biochemistry & Molecular Biology
Adam Azlan, Yaashini Rajasegaran, Khor Kang Zi, Aliaa Arina Rosli, Mot Yee Yik, Narazah Mohd Yusoff, Olaf Heidenreich, Emmanuel Jairaj Moses
Summary: This review highlights the dysregulation mechanisms of miRNAs in cancer and discusses the advantages and disadvantages of various molecular genetics tools for studying miRNA function, focusing on CRISPR/Cas systems. It provides general workflows and practical considerations to help researchers choose the appropriate tools for their experiments.
Article
Biochemistry & Molecular Biology
Daniel Rico, Daniel Kent, Nefeli Karataraki, Aneta Mikulasova, Rolando Berlinguer-Palmini, Brian A. Walker, Biola M. Javierre, Lisa J. Russell, Chris A. Brackley
Summary: This study used a predictive model to predict chromatin conformation of the proto-oncogene CCND1 in both healthy and malignant B cells, and found that genomic rearrangements involving CCND1 can lead to chromatin remodeling and oncogene activation.
Review
Oncology
Isobelle Wall, Victoire Boulat, Aekta Shah, Kim R. M. Blenman, Yin Wu, Elena Alberts, Dinis Pedro Calado, Roberto Salgado, Anita Grigoriadis
Summary: The tumor microenvironment (TME), lymph nodes (LNs), and peripheral blood form the interconnected immune sites in breast cancer. Understanding the dynamic interaction between these immune sites is crucial for improving anti-cancer responses and therapeutic outcomes in breast cancer patients.
Article
Oncology
Emma J. Verwaaijen, Patrick van der Torre, Josef Vormoor, Rob Pieters, Marta Fiocco, Annelies Hartman, Marry M. van den Heuvel-eibrink
Summary: Children treated for hemato-oncological diseases are at risk of muscle deterioration. The pediatric SARC-F (PED-SARC-F) is an accurate screening tool for identifying functional sarcopenia in these patients. A cut-off point of >= 5 has the highest specificity and reduces unnecessary assessments.
Article
Oncology
Hasan Issa, Laura E. E. Swart, Milad Rasouli, Minoo Ashtiani, Sirintra Nakjang, Nidhi Jyotsana, Konstantin Schuschel, Michael Heuser, Helen Blair, Olaf Heidenreich
Summary: Hallmarks of AML include chromosomal rearrangements generating fusion genes, which are ideal therapeutic targets but difficult to treat conventionally. This study demonstrates the use of siRNA-loaded lipid nanoparticles to specifically target the leukaemic fusion gene RUNX1/ETO. Inhibition of RUNX1/ETO resulted in extended survival, reduced leukaemic proliferation, induced differentiation and impaired re-engraftment potential in vivo. These findings provide proof for targeting RUNX1/ETO and support further development of siRNA-LNPs for fusion gene-driven malignancies.
Article
Pharmacology & Pharmacy
Laura E. Swart, Marcel H. A. M. Fens, Anita van Oort, Piotr Waranecki, L. Daniel Mata Casimiro, David Tuk, Martijn Hendriksen, Luca van den Brink, Elizabeth Schweighart, Cor Seinen, Ryan Nelson, Anja Krippner-Heidenreich, Tom O'Toole, Raymond M. Schiffelers, Sander Kooijmans, Olaf Heidenreich
Summary: Lipid nanoparticles (LNPs) are rapidly evolving as promising delivery systems for oligonucleotides, including siRNAs. In this study, LNPs were specifically targeted to hematopoietic progenitor cells in the bone marrow using a modified tripeptide ligand. Functionalized LNPs showed improved uptake and delivery of siRNA in patient-derived leukemia cells, as well as increased accumulation and retention in the bone marrow. These findings suggest the potential of LNPs for targeted therapy in leukemia and other hematological disorders.
Article
Oncology
Ruth Fluemann, Julia Hansen, Benedikt W. Pelzer, Pascal Nieper, Tim Lohmann, Ilmars Kisis, Tobias Riet, Viktoria Kohlhas, Phuong-Hien Nguyen, Martin Peifer, Nima Abedpour, Graziella Bosco, Roman K. Thomas, Moritz Kochanek, Jacqueline Knufer, Lorenz Jonigkeit, Filippo Beleggia, Alessandra Holzem, Reinhard Buttner, Philipp Lohneis, Jorn Meinel, Monika Ortmann, Thorsten Persigehl, Michael Hallek, Dinis Pedro Calado, Markus Chmielewski, Sebastian Klein, Joachim R. Goethert, Bjoern Chapuy, Branko Zevnik, F. Thomas Wunderlich, Bastian von Tresckow, Ron D. Jachimowicz, Ari M. Melnick, Hans Christian Reinhardt, Gero Knittel
Summary: Genomic profiling identified 5 subtypes of DLBCL, including the MCD/C5 cluster with MYD88, BCL2, PRDM1, and/or SPIB aberrations. Mouse models with B cell-specific Prdm1 or Spib aberrations were generated, showing molecular features of prememory and light-zone B cells. Combined BTK/BCL2 inhibition exhibited therapeutic activity in both mouse models and relapsed/refractory DLBCL patients.
BLOOD CANCER DISCOVERY
(2023)
Meeting Abstract
Pediatrics
E. Law, L. McKenzie, H. Blair, K. Szoltysek, M. Singh, S. Bomken, J. Lunec, J. Irving, J. Vormoor, O. Heidenreich
KLINISCHE PADIATRIE
(2022)
Article
Medicine, Research & Experimental
Annalisa D'Avola, Nathalie Legrave, Mylene Tajan, Probir Chakravarty, Ryan L. Shearer, Hamish W. King, Katarina Kluckova, Eric C. Cheung, Andrew J. Clear, Arief S. Gunawan, Lingling Zhang, Louisa K. James, James MacRae, John G. Gribben, Dinis P. Calado, Karen H. Vousden, John C. Riches
Summary: The synthesis of serine from glucose plays a crucial role in cellular proliferation and is important in germinal center biology. This study shows that upregulation of serine synthesis pathway is a metabolic hallmark of B cell activation and the germinal center reaction, and inhibiting the key enzyme PHGDH leads to defective germinal formation and impaired antibody production. Furthermore, overexpression of enzymes involved in serine synthesis is characteristic of germinal center B cell-derived lymphomas, and inhibiting PHGDH can induce apoptosis in lymphoma cells, reducing disease progression.
JOURNAL OF CLINICAL INVESTIGATION
(2022)