Article
Oncology
Yanbo Nie, Liang Shao, Hong Zhang, Colin K. He, Hongyu Li, Junyan Zou, Long Chen, Huaiyue Ji, Hao Tan, Yani Lin, Kun Ru
Summary: CMML patients in China exhibit a unique mutational spectrum, with common mutations in epigenetic modifiers (TET2 and ASXL1), signaling transduction pathway components (NRAS), and splicing factor (SRSF2). DNMT3A, ETV6, FLT3, and NPM1 mutations are associated with progression to sAML. ASXL1 mutation and treatment modalities are independent prognostic factors for CMML.
EXPERIMENTAL HEMATOLOGY & ONCOLOGY
(2022)
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
Hematology
Shrinidhi Nathany, Gaurav Chatterjee, Shruti Ghai, Nirmalya Roy Moulik, Dhanalaxmi Shetty, P. G. Subramanian, Prashant Tembhare, Sumeet Gujral, Chetan Dhamne, Sripad Banavali, Gaurav Narula, Nikhil Patkar
Summary: Juvenile myelomonocytic leukemia (JMML) is a rare childhood neoplasm categorized under myelodysplastic/myeloproliferative neoplasms. A low-cost targeted myeloid panel was developed to comprehensively evaluate the genomic profile of JMML, revealing that almost 90% of patients have at least one mutation, with the most common mutations found in RAS/MAPK-pathway genes. Monosomy 7 was detected in 32% of patients, with implications for overall survival.
INTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY
(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)
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)
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.
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
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
Rieko Taniguchi, Hideki Muramatsu, Yusuke Okuno, Taro Yoshida, Manabu Wakamatsu, Motoharu Hamada, Chiyoe Shirota, Wataru Sumida, Akinari Hinoki, Takahisa Tainaka, Yoshimitsu Gotoh, Toyonori Tsuzuki, Yukichi Tanaka, Seiji Kojima, Hiroo Uchida, Yoshiyuki Takahashi
Summary: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is caused by germline variants in the fumarate hydratase (FH) gene. A seven-year-old boy with a large right kidney tumor underwent nephrectomy and recovered well without metastasis or recurrence, making him the youngest-onset case of HLRCC-associated RCC reported to date. This case may impact future RCC surveillance programs for patients with HLRCC.
Article
Oncology
Takayo Urata, Toshihiko Imamura, Shinya Osone, Hideki Muramatsu, Yoshiyuki Takahashi, Hajime Hosoi
Summary: Fanconi anemia (FA) is a rare genetic disorder characterized by congenital abnormalities and bone marrow failure (BMF). Recent studies have found that defective ALDH2 variant accelerates the development of BMF in patients with FA.
JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY
(2022)
Article
Hematology
Asahito Hama, Daisuke Hasegawa, Atsushi Manabe, Kazue Nozawa, Atsushi Narita, Hideki Muramatsu, Yoshiyuki Kosaka, Masao Kobayashi, Katsuyoshi Koh, Yoshiyuki Takahashi, Kenichiro Watanabe, Akira Ohara, Masafumi Ito, Seiji Kojima
Summary: The study found that childhood refractory cytopenia of childhood (RCC) can be divided into two categories: RCC without multilineage dysplasia (RCC-w/o-MLD) and RCC with multilineage dysplasia (RCC-MLD). Patients in both categories typically have a high incidence of chromosomal abnormalities at diagnosis and a significant risk of secondary graft failure after hematopoietic cell transplantation.
BRITISH JOURNAL OF HAEMATOLOGY
(2022)
Article
Oncology
Antonio Bruno Alves-Silva, Bruna Alves Fenerich, Natasha Peixoto Fonseca, Jaqueline Cristina Fernandes, Juan Luiz Coelho-Silva, Diego Antonio Pereira-Martins, Thiago Mantello Bianco, Priscila Santos Scheucher, Eduardo Magalhaes Rego, Fernando Chahud, Joao Agostinho Machado-Neto, Lorena Lobo Figueiredo-Pontes, Fabiola Traina
Summary: This study investigated the effects of phenformin on Jak2(V617F)-knockin MPN mice. The results showed that phenformin increased the percentages of LSK, MP, and MPP populations in the bone marrow, but did not reduce the disease burden. Further studies are needed to understand the effects of phenformin on early hematopoietic progenitors.
INVESTIGATIONAL NEW DRUGS
(2022)
Article
Hematology
Diego A. Pereira-Martins, Juan L. Coelho-Silva, Isabel Weinhauser, Pedro L. Franca-Neto, Douglas R. Silveira, Cesar Ortiz, Amanda Moreira-Aguiar, Marinus M. Lima, Luisa C. Koury, Raul A. de Melo, Ana B. Gloria, Evandro M. Fagundes, Bruno K. Lino, Katia Pagnano, Rosane Bittencourt, Elenaide Nunes, Fabiola Traina, Lorena Figueiredo-Pontes, Armand Keating, Martin S. Tallman, Raul C. Ribeiro, Richard Dilon, Arnold Ganser, Miguel A. Sanz, Nancy Berliner, Peter Valk, Bob Lowenberg, Tiziana Ottone, Nelida Noguera, Maria T. Voso, Francesca Paoloni, Paola Fazi, Emanuele Ammatuna, Gerwin Huls, Jan Jacob Schuringa, Eduardo M. Rego, Antonio R. Lucena-Araujo
Summary: A growing body of evidence indicates that higher-than-normal mitochondrial DNA content (mtDNAc) is associated with better prognosis in acute promyelocytic leukemia (APL) patients, regardless of tumor burden. This effect is more pronounced in low-risk patients. The multivariate Cox proportional hazard model reveals that high mtDNAc is independently associated with a decreased cumulative incidence of relapse. These findings highlight the potential role of mitochondrial metabolism in APL patients treated with ATRA.
BRITISH JOURNAL OF HAEMATOLOGY
(2023)
Article
Oncology
Shuichi Ozono, Kazuo Sakashita, Nao Yoshida, Harumi Kakuda, Kenichiro Watanabe, Miho Maeda, Yasushi Ishida, Atsushi Manabe, Takashi Taga, Hideki Muramatsu
Summary: In this study, a questionnaire was used to investigate the late effects in survivors of allogenic hematopoietic stem cell transplantation (HSCT) for juvenile myelomonocytic leukemia (JMML). The results showed that approximately 83% of the survivors experienced more than one late effect, including endocrine, dental, skin, ophthalmologic, musculoskeletal, pulmonary, neurocognitive, and cardiovascular dysfunction. The prevalence of short stature, pulmonary, cardiovascular, and nephrological complications was significantly higher among survivors who were more than 12 years post-HSCT. Therefore, establishing a multidisciplinary follow-up system for survivors of JMML is crucial.
PEDIATRIC BLOOD & CANCER
(2023)
Letter
Hematology
Ayako Yamamori, Motoharu Hamada, Hideki Muramatsu, Manabu Wakamatsu, Asahito Hama, Atsushi Narita, Yusuke Tsumura, Taro Yoshida, Takehiko Doi, Kazuki Terada, Takeshi Higa, Nobuyuki Yamamoto, Hiroki Miura, Mitsutaka Shiota, Kenichiro Watanabe, Nao Yoshida, Ryo Maemura, Masayuki Imaya, Shunsuke Miwata, Kotaro Narita, Shinsuke Kataoka, Rieko Taniguchi, Kyogo Suzuki, Nozomu Kawashima, Nobuhiro Nishio, Hideto Iwafuchi, Masafumi Ito, Seiji Kojima, Yusuke Okuno, Yoshiyuki Takahashi
AMERICAN JOURNAL OF HEMATOLOGY
(2023)
Article
Medicine, General & Internal
Sosuke Arakawa, Makoto Nakao, Kazuki Sone, Shuntaro Hayashi, Masahiro Sugihara, Yuya Hirata, Mamiko Kuriyama, Norihisa Takeda, Kazuhiro Ohtakara, Yoshimi Horikawa, Hideki Muramatsu
Summary: A 77-year-old man presented with cough, pharyngeal discomfort, and weight loss for 1 month. Chest radiography showed a mass shadow in the right upper lung field. Bronchoscopy revealed multiple white nodules along the tracheal cartilage ring. Adenocarcinoma cells were detected in the mass, but no malignancy was found in several biopsy specimens of the tracheal lesions. F-18-fluorodeoxyglucose positron emission tomography showed intense accumulation in the mass, nasal septum, and tracheal cartilage. Furthermore, the patient had elevated levels of anti-type II collagen antibody. He was finally diagnosed with lung cancer complicated by relapsing polychondritis. The treatment included oral prednisolone and sequential chemoradiotherapy for lung cancer.
Article
Hematology
Motoharu Hamada, Hideki Muramatsu, Yuka Torii, Kyogo Suzuki, Atsushi Narita, Taro Yoshida, Masayuki Imaya, Ayako Yamamori, Manabu Wakamatsu, Shunsuke Miwata, Kotaro Narita, Shinsuke Kataoka, Nozomu Kawashima, Rieko Taniguchi, Eri Nishikawa, Nobuhiro Nishio, Yoshinori Ito, Seiji Kojima, Yoshiyuki Takahashi
Summary: This single-center retrospective study evaluated the outcomes of 30 children who underwent bone marrow transplantation from HLA 7/8-matched unrelated donors with rATG as GVHD prophylaxis. The results showed favorable outcomes and acceptable GVHD, indicating the feasibility of this approach.
INTERNATIONAL JOURNAL OF HEMATOLOGY
(2023)
Review
Hematology
Taro Fukuta, Hideki Muramatsu, Daiki Yamashita, Daichi Sajiki, Ryo Maemura, Yusuke Tsumura, Ayako Yamamori, Masayuki Imaya, Manabu Wakamatsu, Eri Nishikawa, Kotaro Narita, Shinsuke Kataoka, Rieko Taniguchi, Atsushi Narita, Nobuhiro Nishio, Yoshiyuki Takahashi
Summary: This article presents a case study of vedolizumab treatment for pediatric intestinal acute graft-versus-host disease (aGVHD). The efficacy of vedolizumab in 10 pediatric patients with intestinal aGVHD was evaluated, and the results showed potential effectiveness of this drug with no serious adverse events.
INTERNATIONAL JOURNAL OF HEMATOLOGY
(2023)
Article
Hematology
Asuka Kono, Manabu Wakamatsu, Yoshihiro Umezawa, Hideki Muramatsu, Hiroki Fujiwara, Dan Tomomasa, Kento Inoue, Keiichiro Hattori, Tetsuo Mitsui, Hidetoshi Takada, Yoshiyuki Minegishi, Yoshiyuki Takahashi, Masahide Yamamoto, Takehiko Mori, Hirokazu Kanegane
Summary: DOCK8 deficiency is a rare genetic immune deficiency characterized by eczema, elevated IgE, and recurrent infections. Two Japanese patients with DOCK8 deficiency were successfully treated by allogeneic HCT from alternative donors, resulting in improved clinical manifestations and successful engraftment and immune reconstitution.
INTERNATIONAL JOURNAL OF HEMATOLOGY
(2023)
Article
Pathology
Kazunori Haruta, Suguru Takeuchi, Makoto Yamaguchi, Kazuhiro Horiba, Takako Suzuki, Yuka Torii, Atsushi Narita, Hideki Muramatsu, Yoshiyuki Takahashi, Yoshinori Ito, Jun-ichi Kawada
Summary: In this study, a novel pathogen detection technology called droplet digital PCR (ddPCR) was developed and compared with real-time quantitative PCR (qPCR) for detecting human adenovirus DNA. The results showed that ddPCR exhibited better reproducibility and sensitivity, as well as equivalent quantifiability, compared with qPCR. Therefore, ddPCR has the potential to provide a more accurate DNAemia detection, determine cutoff values for treatment initiation, and enable antiviral efficacy assessment.
JOURNAL OF MOLECULAR DIAGNOSTICS
(2023)
Article
Oncology
Shinsaku Imashuku, Shin-ichiro Suemori, Manabu Wakamatsu, Yusuke Okuno, Hideki Muramatsu, Shigeru Makino, Takashi Miyoshi, Kazuhisa Chonabayashi, Hitoshi Kanno
Summary: Differential diagnosis of juvenile hemochromatosis with hemolytic anemia is challenging. We present a case of a 23-year-old woman with macrocytic hemolytic anemia and iron overload. A mutation in the PIEZO1 gene (heterozygous c.6008C>A: p.A2003D) was identified through target gene sequencing, which has been previously reported in a family with dehydrated hereditary stomatocytosis (DHS1, [OMIM 194380]). This case highlights the importance of considering DHS1 in the differential diagnosis of iron overload associated with non-transfused hemolytic anemia in children and young adults.
JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY
(2023)
Letter
Oncology
Hiromi Tobai, Mikiya Endo, Masataka Ishimura, Kunihiko Moriya, Jun Yano, Keita Kanamori, Norio Sato, Fumitaka Amanuma, Hidekazu Maruyama, Hideki Muramatsu, Junji Shibahara, Masami Narita, Seiko Fumoto, Daniel Peltier, Shouichi Ohga
PEDIATRIC BLOOD & CANCER
(2023)
Article
Clinical Neurology
Hiroyuki Yamamoto, Jun Natsume, Kimihiko Kaneko, Toshiyuki Takahashi, Manabu Wakamatsu, Chikako Ogawa, Sumire Kumai, Ryosuke Suzui, Fumi Sawamura, Anna Shiraki, Tomohiko Nakata, Hiroyuki Kidokoro, Hideki Muramatsu, Yoshiyuki Takahashi
Summary: This study reports two rare cases of patients with juvenile myelomonocytic leukemia (JMML) who developed myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). We propose that abnormalities in the RAS pathway contribute to the formation of anti-MOG antibodies and the onset of MOGAD.
PEDIATRIC NEUROLOGY
(2023)