Article
Oncology
Maximilian Schoenung, Julia Meyer, Peter Noellke, Adam B. Olshen, Mark Hartmann, Norihiro Murakami, Manabu Wakamatsu, Yusuke Okuno, Christoph Plass, Mignon L. Loh, Charlotte M. Niemeyer, Hideki Muramatsu, Christian Flotho, Elliot Stieglitz, Daniel B. Lipka
Summary: DNA methylation patterns in JMML can serve as a biomarker for patient stratification. This study established three DNA methylation subgroups and developed a classifier with 98% accuracy, which can classify patients across different technological platforms to guide clinical treatment decisions.
CLINICAL CANCER RESEARCH
(2021)
Article
Immunology
Eleni Louka, Benjamin Povinelli, Alba Rodriguez-Meira, Gemma Buck, Wei Xiong, Guanlin Wang, Nikolaos Sousos, Neil Ashley, Angela Hamblin, Christopher A. G. Booth, Anindita Roy, Natalina Elliott, Deena Iskander, Josu de la Fuente, Nicholas Fordham, Sorcha O'Byrne, Sarah Inglott, Ruggiero Norfo, Mariolina Salio, Supat Thongjuea, Anupama Rao, Irene Roberts, Adam J. Mead
Summary: Juvenile myelomonocytic leukemia (JMML) is a childhood leukemia with poor prognosis caused by RAS-pathway mutations. The cellular hierarchy of JMML is complex, with LSCs present in HSPCs, providing new avenues for monitoring and treating the disease.
JOURNAL OF EXPERIMENTAL MEDICINE
(2021)
Article
Cell Biology
Anna Dal Molin, Mattias Hofmans, Enrico Gaffo, Alessia Buratin, Helene Cave, Christian Flotho, Valerie de Haas, Charlotte M. Niemeyer, Jan Stary, Pieter Van Vlierberghe, Jan Philippe, Barbara De Moerloose, Geertruij te Kronnie, Silvia Bresolin, Tim Lammens, Stefania Bortoluzzi
Summary: JMML is characterized by clonal growth of RAS signaling addicted stem cells, with specific mutations defining subtypes and distinct gene, miRNA, and long non-coding RNA expression profiles. This study focused on circRNAs, identifying dysregulated circRNAs and showing expression differences among molecular subgroups of JMML. Validation in an independent cohort confirmed up-regulation of circMCTP1 and its connection to tumor suppressor miRNAs, linking dysregulated circRNAs to regulatory networks.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Review
Oncology
Claudia Finana, Noel Gomez-Molina, Sandra Alonso-Moreno, Laura Belver
Summary: Juvenile myelomonocytic leukemia (JMML) is a rare childhood blood cancer characterized by RAS signaling hyperactivation and genetic and epigenetic alterations. The recent international consensus on JMML stratification has classified the disease into three clinical groups based on DNA methylation status. However, our understanding of JMML origin, cell identity, and heterogeneity remains limited.
Article
Biotechnology & Applied Microbiology
Santhosh Kumar Pasupuleti, Karen Chao, Baskar Ramdas, Rahul Kanumuri, Lakshmi Reddy Palam, Sheng Liu, Jun Wan, Colleen Annesley, Mignon L. Loh, Elliot Stieglitz, Michael J. Burke, Reuben Kapur
Summary: Juvenile myelomonocytic leukemia (JMML) is a rare childhood disease characterized by hyperactivation of the Ras/MAPK pathway. Current treatment strategies for JMML, such as the use of hypomethylating agents or MEK inhibitors, are not curative as monotherapy. In this study, a combination treatment of 5-Aza and PD-901 was found to improve hematologic abnormalities and reduce leukemic cells in a murine model of JMML. Furthermore, this combination treatment also showed clinical response in two JMML patients with PTPN11 mutations.
Review
Medicine, General & Internal
Leila Cardoso, Victor Galan-Gomez, Maria Dolores Corral-Sanchez, Antonio Perez-Martinez, Susana Riesco, Maria Isidoro-Garcia, Adela Escudero
Summary: The clinical and laboratory criteria for hemophagocytic lymphohistiocytosis should be considered in the diagnosis of juvenile myelomonocytic leukemia, especially in CBL syndrome, to distinguish primary from secondary associated hemophagocytosis.
CLINICAL CASE REPORTS
(2021)
Review
Medicine, General & Internal
Christina Mayerhofer, Charlotte M. Niemeyer, Christian Flotho
Summary: JMML is a rare pediatric leukemia characterized by mutations in RAS pathway genes, with treatment options based on genetic profile and disease severity. Management can include medication or allogeneic hematopoietic stem cell transplantation tailored to individual patient needs.
JOURNAL OF CLINICAL MEDICINE
(2021)
Review
Hematology
Astrid Wintering, Christopher C. Dvorak, Elliot Stieglitz, Mignon L. Loh
Summary: Juvenile myelomonocytic leukemia is a complex disease with diverse clinical outcomes, ranging from spontaneous resolution to transformation to acute myeloid leukemia. Next-generation sequencing allows for more accurate molecular diagnoses, but curative treatment still relies on allogeneic hematopoietic cell transplantation for most patients. Further advances are needed to improve risk stratification algorithms for better management of the disease.
Article
Oncology
Ying Wu, Patricia M. A. Zehnle, Jovana Rajak, Naile Koleci, Geoffroy Andrieux, Lorena Gallego-Villar, Konrad Aumann, Melanie Boerries, Charlotte M. Niemeyer, Christian Flotho, Sheila Bohler, Miriam Erlacher
Summary: JMML cells rely on both MCL-1 and BCL-XL for survival, and azacitidine and BH3 mimetic drugs can effectively target these proteins. Azacitidine acts in vivo through downregulation of MCL-1 and upregulation of BH3-only. Combination treatment of azacitidine with BCL-XL inhibition is more effective in eliminating JMML cells compared to BCL-2 inhibition. These findings highlight the need for clinically applicable MCL-1 or BCL-XL inhibitors in JMML refractory to standard therapy.
Article
Multidisciplinary Sciences
Mattias Hofmans, Tim Lammens, Barbara Depreter, Ying Wu, Miriam Erlacher, Aurelie Caye, Helene Cav, Christian Flotho, Valerie de Haas, Charlotte M. Niemeyer, Jan Stary, Filip Van Nieuwerburgh, Dieter Deforce, Wouter Van Loocke, Pieter Van Vlierberghe, Jan Philipp, Barbara De Moerloose
Summary: In this study, targeting overexpressed long non-coding RNAs (lncRNAs) in JMML was investigated as a therapeutic strategy. Knockdown of three lncRNAs (lnc-THADA-4, lnc-ACOT9-1, and NRIR) resulted in a significant decrease in cell viability in primary JMML cell cultures, with cellular damage correlating with the expression level of the lncRNA of interest. This study suggests that targeting overexpressed lncRNAs may be a viable therapeutic approach for JMML.
SCIENTIFIC REPORTS
(2021)
Article
Chemistry, Medicinal
Jose-Manuel Gally, Axel Pahl, Paul Czodrowski, Herbert Waldmann
Summary: This study introduces a new methodology for classifying fragment combinations and characterizing pseudonatural products using Python package. By analyzing the pairwise relative position of fragments within molecules, 18 different possible fragment combination categories were identified. Comparison with natural product references revealed that approximately 23% of biologically relevant compounds in the database comply with the PNP definition.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)
Review
Oncology
Sagarajit Mohanty, Michael Heuser
Summary: Acute myeloid leukemia is a biologically diverse blood cancer with variable prognosis, and comprehensive sequencing and mouse models play crucial roles in understanding the genetic mechanisms and drug targets in AML. This review focuses on the leukemogenic function of mutations in seven functional gene groups using evidence from mouse models, providing insights into the cooperative mutations in AML development and their correlation with prognosis.
Article
Hematology
Anna Hecht, Julia A. Meyer, Astrid Behnert, Eric Wong, Farid Chehab, Adam Olshen, Aaron Hechmer, Catherine Aftandilian, Rukhmi Bhat, Sung Won Choi, Satheesh Chonat, Jason E. Farrar, Mark Fluchel, Haydar Frangoul, Jennifer H. Han, Edward A. Kolb, Dennis J. Kuo, Margaret L. MacMillan, Luke Maese, Kelly W. Maloney, Aru Narendran, Benjamin Oshrine, Kirk R. Schultz, Maria L. Sulis, David Van Mater, Sarah K. Tasian, Wolf-Karsten Hofmann, Mignon L. Loh, Elliot Stieglitz
Summary: Mutations in the CBL gene can lead to various myeloid malignancies, with some pediatric patients with JMML carrying CBL mutations but having milder disease courses. The majority of CBL mutations in JMML patients are germline, not somatic mutations. The disease presentation and overall outcome of JMML patients with CBL mutations are highly diverse, and some patients have more aggressive disease with somatically acquired CBL mutations. Clinical features and methylation profiling cannot accurately distinguish patients with different types of CBL mutations, highlighting the need for germline testing.
Article
Hematology
Charlotte M. Niemeyer, Christian Flotho, Daniel B. Lipka, Jan Stary, Claudia Rossig, Andre Baruchel, Thomas Klingebiel, Concetta Micalizzi, Gerard Michel, Karsten Nysom, Susana Rives, Markus Schmugge Liner, Marco Zecca, Maximilian Schoenung, Irith Baumann, Peter Nollke, Bouchra Benettaib, Noha Biserna, Jennifer Poon, Mathew Simcock, Meera Patturajan, Daniel Menezes, Allison Gaudy, Marry M. Van den Heuvel-Eibrink, Franco Locatelli
Summary: Azacitidine monotherapy is a feasible option for children with newly diagnosed JMML, providing valuable clinical benefits prior to HSCT. Long-term safety and efficacy data in this population are still needed for full elucidation.
Review
Oncology
Nele De Vos, Mattias Hofmans, Tim Lammens, Bram De Wilde, Nadine Van Roy, Barbara De Moerloose
Summary: Juvenile myelomonocytic leukemia (JMML) is a rare and aggressive childhood tumor, and targeted therapy may be an important approach for future treatment of the disease.
PEDIATRIC BLOOD & CANCER
(2022)
Review
Oncology
Serena Ilaria Tripodi, Elena Bergami, Arianna Panigari, Valentina Caissutti, Carlotta Brovia, Marica De Cicco, Emanuele Cereda, Riccardo Caccialanza, Marco Zecca
Summary: Nutrition plays an increasingly important role in the health and growth of children, especially those facing cancer. This article reviews nutritional assessment methods and interventions for children with cancer. The key findings highlight the importance of monitoring the nutritional status and body composition of oncologic children, as well as the need for skilled clinical nutrition personnel.
Letter
Oncology
Kentaro Ohki, Ellie R. Butler, Nobutaka Kiyokawa, Shinsuke Hirabayashi, Anke K. Bergmann, Anja Moericke, Judith M. Boer, Helene Cave, Giovanni Cazzaniga, Allen Eng Juh Yeoh, Masashi Sanada, Toshihiko Imamura, Hiroto Inaba, Charles G. Mullighan, Mignon L. Loh, Ulrika Noren-Nystrom, Lee-Yung Shih, Marketa Zaliova, Ching-Hon Pui, Oskar A. Haas, Christine J. Harrison, Anthony V. Moorman, Atsushi Manabe
Article
Clinical Neurology
Anne Sophie L. Helligsoe, Louise T. Henriksen, Line Kenborg, Yasmin Lassen-Ramshad, Lisa M. Wu, Jeanette F. Winther, Henrik Hasle, Ali Amidi
Summary: This study examined neurocognitive function in childhood brain tumor survivors and its associations with quality of life (QoL) and symptom burden. The majority of survivors exhibited overall neurocognitive impairment, reduced QoL, and high symptom burden.
NEURO-ONCOLOGY PRACTICE
(2023)
Article
Hematology
David Spencer Mangum, Johnathon D. Bishop, Yinmei Zhou, Cheng Cheng, Seth E. Karol, Jeffrey E. Rubnitz, Raul C. Ribeiro, Jun J. Yang, Charles G. Mullighan, Sima Jeha, Ching-Hon Pui, Hiroto Inaba
Summary: Among children with acute lymphoblastic leukaemia, about 14.7% presented without peripheral blood blasts. While absence of blasts did not affect survival outcomes, these patients had distinct genetic and clinical characteristics, with a higher incidence of hyperdiploid B-ALL and lower rates of central nervous system involvement.
BRITISH JOURNAL OF HAEMATOLOGY
(2023)
Review
Pathology
Amy S. Duffield, Charles G. Mullighan, Michael J. Borowitz
Summary: The updated International Consensus Classification (ICC) of B-acute lymphoblastic leukemia (B-ALL) and T-acute lymphoblastic leukemia (T-ALL) includes revisions to previous subtypes and new entities. The classification incorporates recent clinical, cytogenetic, and molecular data, emphasizing whole transcriptome analysis and gene expression clustering studies. The new classification allows for improved risk stratification and optimized treatment plans for ALL patients.
Letter
Hematology
Sai Prasad Desikan, Jayastu Senapati, Elias Jabbour, Tareq Abuasab, Nicholas Short, Guilin Tang, Sa Wang, Partow Kebriaei, Tapan Kadia, Gautam Borthakur, Farhad Ravandi, Kathryn Roberts, Charles Mullighan, Marina Konopleva, Hagop Kantarjian, Nitin Jain
AMERICAN JOURNAL OF HEMATOLOGY
(2023)
Letter
Hematology
Olga K. Weinberg, Daniel A. Arber, Hartmut Doehner, Charles G. Mullighan, Etan Orgel, Anna Porwit, Richard M. Stone, Michael J. Borowitz
Letter
Biophysics
Luca Vinci, Christian Flotho, Peter Noellke, Dirk Lebrecht, Riccardo Masetti, Valerie de Haas, Barbara De Moerloose, Michael Dworzak, Henrik Hasle, Tayfun Guengoer, Jan Stary, Dominik Turkiewicz, Marek Ussowicz, Cristina Diaz de Heredia, Jochen Buechner, Kirsi Jahnukainen, Krisztian Kallay, Ivana Bodova, Owen P. P. Smith, Marco Zecca, Dorine Bresters, Peter Lang, Tania Nicole Masmas, Roland Meisel, Herbert Pichler, Miriam Erlacher, Gudrun Goehring, Franco Locatelli, Brigitte Strahm, Charlotte M. M. Niemeyer, Ayami Yoshimi
BONE MARROW TRANSPLANTATION
(2023)
Article
Hematology
Sarah Weischendorff, Silvia De Pietri, Mathias Rathe, Thomas Leth Frandsen, Henrik Hasle, Claus H. Nielsen, Claus Moser, Klaus Mueller
Summary: This study investigated whether measurements of neutrophil chemotaxis could be used as risk markers for bloodstream infections (BSI) in children with acute lymphoblastic leukemia (ALL). The results showed that patients who developed BSI during induction treatment had increased levels of chemokines CXCL1 and CXCL8, suggesting that these markers may help identify patients at increased risk of BSI during chemotherapy-induced neutropenia.
EUROPEAN JOURNAL OF HAEMATOLOGY
(2023)
Article
Oncology
Satoshi Yoshimura, John C. Panetta, Jianzhong Hu, Lie Li, Yoshihiro Gocho, Guoqing Du, Akihiro Umezawa, Seth E. Karol, Ching-Hon Pui, Charles G. Mullighan, Marina Konopleva, Wendy Stock, David T. Teachey, Nitin Jain, Jun J. Yang
Summary: LCK is a therapeutic target in T-cell acute lymphoblastic leukemia (T-ALL), and dasatinib and ponatinib are effective inhibitors of LCK. This study evaluates the pharmacokinetics and pharmacodynamics of dasatinib and ponatinib in LCK-activated T-ALL. Both drugs demonstrate similar cytotoxic activity, with ponatinib being slightly more potent. Ponatinib exhibits slower clearance and higher exposure compared to dasatinib. Exposure-to-response models suggest that both drugs achieve significant pLCK inhibition, comparable to their effects in other leukemias. Additionally, ponatinib retains partial activity against LCK in a dasatinib-resistant T-ALL cell line model. Overall, this study provides crucial data for the development of human trials involving dasatinib and ponatinib in T-ALL.
Article
Biophysics
Karl-Walter Sykora, Rita Beier, Ansgar Schulz, Simone Cesaro, Johann Greil, Jolanta Gozdzik, Petr Sedlacek, Peter Bader, Johannes Schulte, Marco Zecca, Franco Locatelli, Bernd Gruhn, Dirk Reinhardt, Jan Styczynski, Simona Piras, Franca Fagioli, Sonia Bonanomi, Maurizio Caniglia, Xieran Li, Joachim Baumgart, Jochen Kehne, Monika Mielcarek-Siedziuk, Krzysztof Kalwak
Summary: This study compared the safety and efficacy of busulfan and treosulfan in conditioning treatment for children with non-malignant diseases prior to hematopoietic stem cell transplantation. The results showed that treosulfan had a higher rate of treatment success and overall survival, but a higher rate of graft failure. Busulfan and treosulfan had similar adverse events.
BONE MARROW TRANSPLANTATION
(2023)
Article
Hematology
V. Munaretto, P. Corti, E. Bertoni, S. I. Tripodi, M. E. Guerzoni, S. Cesaro, F. Arcioni, C. Piccolo, T. Mina, M. Zecca, D. Cuzzubbo, M. Casale, G. Palazzi, L. D. Notarangelo, N. Masera, P. Samperi, S. Perrotta, G. Russo, L. Sainati, R. Colombatti
Summary: Acute chest syndrome (ACS) is a common reason for hospitalization in sickle cell disease (SCD). Despite advances in acute care, many settings lack knowledge about ACS best practices. A retrospective study in Italy showed that standardized management improved diagnostic and therapeutic pathways of ACS in children, but discrepancies were found between reference centers and general hospitals.
BRITISH JOURNAL OF HAEMATOLOGY
(2023)
Article
Oncology
Thomas N. N. Nissen, Catherine Rechnitzer, Birgitte K. K. Albertsen, Lotte Borgwardt, Vibeke B. B. Christensen, Eva Fallentin, Henrik Hasle, Lars S. S. Johansen, Lisa L. L. Maroun, Karin B. B. Nissen, Allan Rasmussen, Mathias Rathe, Steen Rosthoj, Nicolai A. A. Schultz, Peder S. S. Wehner, Marianne H. H. Jorgensen, Jesper Brok
Summary: This study reports the incidence, outcomes, and long-term adverse events of malignant liver tumors in Danish children over the past 35 years. The overall incidence of liver tumors in Danish children was approximately 2.29 per 1 million children per year, with hepatoblastoma being the most common tumor. The overall 5-year survival rate was 84% and 78% for hepatoblastomas and hepatocellular carcinomas, respectively, with age≥8 years being the most significant factor associated with a poorer prognosis. Adverse events included reduced renal and cardiac function, as well as impaired hearing function, affecting a significant number of patients.
Article
Pediatrics
Chiara Ionio, Francesca Bigoni, Maddalena Sacchi, Marco Zecca, Elena Bergami, Marta Landoni, Giulia Ciuffo, Anna Rovati, Damiano Rizzi
Summary: This study aimed to explore the psychological and post-traumatic consequences of oncological disease in adolescents and their impact on the family system. The findings revealed that adolescent cancer patients had lower levels of psychological well-being and showed a significant influence of the traumatic event on their identity and life perspectives. The study also highlighted a positive correlation between adolescents' psychological well-being and their relationship with parents.
Article
Biotechnology & Applied Microbiology
Himani Vaidya, Hye Seon Jeong, Kelsey Keith, Shinji Maegawa, Gennaro Calendo, Jozef Madzo, Jaroslav Jelinek, Jean-Pierre J. Issa
Summary: DNA methylation drift and increased entropy with age are primarily caused by and are sensors for, stem cell replication in adult tissues. These findings have implications for tissue-specific functional declines with aging and the development of DNA-methylation-based biological clocks.