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
Genetics & Heredity
Marwan M. Ali, Amy E. Gilliam, Beth S. Ruben, William E. Tidyman, Katherine A. Rauen
Summary: Noonan syndrome (NS) and neurofibromatosis type 1 (NF1) both have dysregulation of the Ras/MAPK pathway, leading to an increased incidence of juvenile myelomonocytic leukemia (JMML). NS individuals may be predisposed to juvenile xanthogranuloma (JXG) due to this common underlying pathogenetic dysregulation.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
(2021)
Article
Biology
Maja Solman, Sasja Blokzijl-Franke, Florian Piques, Chuan Yan, Qiqi Yang, Marion Strullu, Sarah M. Kamel, Pakize Ak, Jeroen Bakkers, David M. Langenau, Helene Cave, Jeroen den Hertog
Summary: This study discovers a common inflammatory response in sporadic JMML patients and syndromic NS zebrafish, which may potentiate the development of MPN and serve as a potential target for JMML therapies.
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)
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
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
Oncology
Zhengjun Zhou, Pengcheng Wang, Rongqi Sun, Jia Li, Zhiqiang Hu, Haoyang Xin, Chubin Luo, Jian Zhou, Jia Fan, Shaolai Zhou
Summary: The interaction between TANs and TAMs enhances the proliferation and invasion abilities of ICC cells, promoting ICC progression. They can produce Oncostatin M and interleukin-11 in co-culture, activating STAT3 signaling in ICC cells, and silencing STAT3 can disrupt the pro-tumor effect of TANs and TAMs on ICC.
JOURNAL FOR IMMUNOTHERAPY OF CANCER
(2021)
Review
Oncology
Klaus Geissler
Summary: Understanding the pathophysiology of malignancies can lead to the development of targeted treatments with higher efficacy and lower toxicity, Chronic myelomonocytic leukemia (CMML) has a complex pathophysiology, and current treatments are mainly unspecific, but preclinical research has identified potential molecular targets that could provide meaningful benefits for certain subgroups of patients.
FRONTIERS IN ONCOLOGY
(2021)
Review
Cell Biology
Zeinab Wehbe, Foued Ghanjati, Christian Flotho
Summary: JMML is a malignant myeloproliferative disorder arising in infants and young children, notoriously refractory to conventional cytostatic therapy. Allogeneic hematopoietic stem cell transplantation remains the mainstay of curative therapy. Alternative therapeutic approaches with small epigenetic molecules have recently entered the stage and show surprising efficacy, highlighting the need for preclinical models to test novel agents.
Article
Hematology
Hironobu Kitazawa, Yusuke Okuno, Hideki Muramatsu, Kosuke Aoki, Norihiro Murakami, Manabu Wakamatsu, Kyogo Suzuki, Kotaro Narita, Shinsuke Kataoka, Daisuke Ichikawa, Motoharu Hamada, Rieko Taniguchi, Nozomu Kawashima, Eri Nishikawa, Atsushi Narita, Nobuhiro Nishio, Asahito Hama, Mignon L. Loh, Elliot Stieglitz, Seiji Kojima, Yoshiyuki Takahashi
Summary: JMML patients were classified into high and low methylation groups using Digital Restriction Enzyme Analysis of Methylation (DREAM), and further divided into different risk groups by a support vector machine (SVM). Patients with HM_SVM profile had significantly poorer 5-year overall survival rate compared to those with LM_SVM profile.
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)
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.