Papers - MORITAKE Hiroshi
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Novel SKIC3 variants in tricho-hepato-enteric syndrome with hemochromatosis Reviewed
Ochiai K., Aoki Y., Yamada N., Aman M., Yamashita A., Yamaguchi M., Nakato D., Takenouchi T., Kosaki K., Kodama Y., Moritake H.
Human Genome Variation 12 ( 1 ) 14 2025.12
Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：Human Genome Variation
Tricho-hepato-enteric syndrome (THES), a rare autosomal recessive disorder caused by variants in the SKIC3 or SKIC2 gene, is characterized by intractable diarrhea, woolly hair, growth restriction and liver disease. Here we report a neonatal case of THES with neonatal hemochromatosis, in which the novel compound heterozygous SKIC3 variants NM_014639.4:c.815_816del p.(Gly272AlafsTer9) and NM_014639.4:c.2284G>A p.(Gly762Arg) were identified. Further research is needed to elucidate the mechanisms underlying iron metabolism dysregulation in THES.
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Age-specific mutation profiles and their prognostic implications in pediatric KMT2A-rearranged acute myeloid leukemia. Reviewed
Shoji K, Yoshida K, Iyoda S, Ishikawa M, Tanaka M, Nobe M, Saito N, Shino Y, Nannya Y, Yamato G, Tsujimoto S, Shiba N, Hayashi Y, Shiozawa Y, Shiraishi Y, Chiba K, Okada A, Tanaka H, Miyano S, Koga Y, Goto H, Terui K, Ito E, Kiyokawa N, Tomizawa D, Taga T, Moritake H, Tawa A, Takita J, Nishikori M, Adachi S, Ogawa S, Matsuo H
Haematologica 2025.10
Language：English Publishing type：Research paper (scientific journal)
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Interference of Intravenous Acetaminophen with Continuous Glucose Monitoring System Reviewed
Matsuyama Misayo, Meiri Satoru, Sawada Hirotake, Masuya Ryuta, Nakame Kazuhiko, Moritake Hiroshi
JMA Journal 8 ( 4 ) 1463 - 1467 2025.10
Language：English Publishing type：Research paper (scientific journal) Publisher：Japan Medical Association / The Japanese Associaiton of Medical Sciences
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盛武 浩
Frontiers in Hematology 4 1668408 2025.9
Language：English Publishing type：Research paper (scientific journal) Publisher：Frontiers Media SA
Background: Epigenetic dysregulation plays a central role in pediatric acute myeloid leukemia (AML), yet its clinical relevance remains underexplored. This study primarily aimed to elucidate the clinical effect of H3K27me3 and H3K4me3 status on pediatric acute myeloid leukemia. We evaluated the prognostic impact of H3K27me3 and H3K4me3 histone trimethylation, along with associated gene expression profiles, in pediatric AML. Methods: We retrospectively analyzed 74 children with newly diagnosed non-FAB M3 and non-Down syndrome AML in a prolonged cohort in Japan. Bone marrow immunohistochemistry assessed H3K27me3 and H3K4me3 expression levels. RNA sequencing was successfully performed on sorted leukemic blasts in six representative cases, owing to limited sample availability. Chemoresistance and epigenetic modulation were evaluated in AML cell lines treated with GSK-J4, a histone demethylase inhibitor. Results: High H3K27me3 expression at diagnosis was significantly associated with superior overall and event-free survival over three years (OS HR 8.0; EFS HR 5.0; both p < 0.01). H3K4me3 levels at diagnosis showed no prognostic impact. Among 14 KMT2A-rearranged cases, all six patients with high H3K27me3 achieved a long-term first remission (median follow-up: 10 years), whereas those with low expression had higher relapse rates. Transcriptomic analysis revealed upregulation of HOXA9, and HOXA-cluster genes and downregulation of ABCB1, in low H3K27me3 samples. In vitro, GSK-J4 increased H3K27me3 and suppressed HOXA9 expression in KG-1 cells, enhancing sensitivity to cytarabine. Conclusion: Low H3K27me3 expression defines a poor-risk group in pediatric AML, potentially via HOXA9-driven dysregulation. H3K27me3 may serve as a prognostic biomarker and potential therapeutic target.
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Yamamoto N, Maeda K, Kimoto Y, Moritake H
BMJ case reports 18 ( 8 ) 2025.8
Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：BMJ Case Reports
Rasmussen encephalitis (RE) is a progressive disease characterised by unilateral brain atrophy, drug-resistant epilepsy, epilepsia partialis continua, hemiparesis and cognitive decline. Early initiation of immunomodulatory therapy is crucial to slow disease progression. However, early formal diagnosis is challenging as it typically requires hemispheric atrophy or brain biopsy. This case reports on a preschool-aged boy with RE who began immunotherapy before demonstrating clear hemispheric atrophy. Follow-up MRI did not indicate global hemispheric atrophy; however, FreeSurfer-based volumetric analysis revealed a decreased left:right hemispheric volume ratio, suggesting early left hemispheric atrophy. Subsequently, intensive immunotherapy was administered. Over 3 years of treatment, the patient exhibited gradual hemispheric atrophy on MRI, along with mild motor and cognitive impairments. Serial FreeSurfer-based volumetric analysis may contribute to detecting subtle hemispheric volume changes in RE, facilitating prompt diagnosis and early initiation of immunotherapy - potentially limiting disease progression.
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Novel SKIC3 variants in tricho-hepato-enteric syndrome with hemochromatosis Reviewed
青木 良則, 阿萬 紫, 山下 篤, 山口 昌俊, 児玉 由紀, 盛武 浩
Human Genome Variation 12 14 2025.7
Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Nature
Tricho-hepato-enteric syndrome (THES), a rare autosomal recessive disorder caused by variants in the SKIC3 or SKIC2 gene, is characterized by intractable diarrhea, woolly hair, growth restriction and liver disease. Here we report a neonatal case of THES with neonatal hemochromatosis, in which the novel compound heterozygous SKIC3 variants NM_014639.4:c.815_816del p.(Gly272AlafsTer9) and NM_014639.4:c.2284G>A p.(Gly762Arg) were identified. Further research is needed to elucidate the mechanisms underlying iron metabolism dysregulation in THES.
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Fauzi YR, Nakahata S, Shimoda K, Matsuura T, Hagiwara S, Inoue K, Moritake H, Morishita K
Biochemical and biophysical research communications 756 151564 2025.2
Language：English Publishing type：Research paper (scientific journal) Publisher：Biochemical and Biophysical Research Communications
Previously, we developed a complete human IgG TFR1 antibody (JST-TFR09/PPMX-T003) that showed a potentially practical therapeutic effect against adult T-cell leukemia/lymphoma (ATLL) in vitro and in vivo. In the present study, to elucidate the molecular mechanism underlying ATLL cell death induced by anti-TFR1 antibodies, we performed comprehensive gene expression analysis and mass spectrometry on ATLL cells treated with PPMX-T003 antibody. These results suggest that PPMX-T003 antibody treatment of ATLL cell lines induces ferroptosis mediated by ferritin degradation. PPMX-T003 antibody-treated ATLL cell lines showed a decrease in ferritin proteins, an increase in ferrous iron (Fe2+), reactive oxygen species (ROS) generation, and malondialdehyde as induction of lipid peroxidation. Moreover, treatment with a ferroptosis inhibitor (ferroportin-1) inhibited the cell death induced by PPMX-T003 antibody in ATLL cells. Furthermore, NCO4A and LC3-II were induced following antibody treatment, and ferritin degradation was inhibited by lysosomal inhibitors, suggesting that ferritin degradation depends on autolysosomal system activation. Here, we introduce ferroptosis as one of the potential mechanisms of PPMX-T003 antibody, which is promising for future therapeutic antibodies targeting a wide range of leukemia and cancers, including ATLL.
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Aoki Y., Kota Y., Shimada M., Taniguchi T., Yamauchi S., Matsusaka M., Hamasuna K., Watanabe Y., Kodama Y., Moritake H.
Children 12 ( 2 ) 2025.2
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Children
Background: Preterm infants often have unstable vital signs and prolonged hospital stays that can hinder parent–infant bonding, especially under COVID-19 restrictions. This study aimed to evaluate whether listening to songs recorded by parents was effective in stabilizing the condition of premature infants. Methods: This randomized controlled study was conducted at the University of Miyazaki Hospital from October 2022 to March 2024 during the COVID-19 pandemic period. The participants were preterm infants born at less than 33 weeks gestation and their parents, all of whom recorded songs. The recorded songs were played daily to the infants in the intervention group, while the control group received usual care. Primary outcomes included vital signs (respiratory rate, pulse oximetry saturation, heart rate) and activity level. Results: Data for 33 preterm infants (intervention, n = 17 [total 749 sessions]; control, n = 16 [total 721 sessions]) were analyzed for changes in vital signs and activity levels. The intervention reduced infants’ respiratory rates (4.1 [95% CI: 2.5–5.6], p < 0.001) and slightly but statistically significantly increased pulse oximetry saturation (0.6 [95% CI: 0.02–1.2], p < 0.044). Conclusions: Recorded parental songs were found to safely stabilize the respiratory status of preterm infants and may serve as an accessible intervention to support parent–infant attachment, particularly in settings with restricted parental visitation.
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Mori K., Maeda K., Kimoto Y., Ikeda T., Honda R., Yoshiura K.I., Moritake H.
Pediatrics International 67 ( 1 ) e70171 2025.1
Language：English Publishing type：Research paper (scientific journal) Publisher：Pediatrics International
DOI： 10.1111/ped.70171
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Lymphatic dysplasia evaluated by indocyanine green lymphography in congenital myotonic dystrophy Reviewed
Tate M., Aoki Y., Ochiai K., Kodama Y., Nakame K., Kodama Y., Moritake H.
Pediatrics International 67 ( 1 ) e70170 2025.1
Authorship：Last author Language：English Publishing type：Research paper (scientific journal) Publisher：Pediatrics International
DOI： 10.1111/ped.70170
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Yokoyama R., Kodama Y., Takamura K., Takahashi M., Tanaka M., Watanabe N., Moritake H.
Journal of Cardiology Cases 31 ( 6 ) 155 - 157 2025
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology Cases
Exercise stress echocardiography (ESE) is a feasible and valuable tool for evaluating subclinical pulmonary hypertension (PH). However, its utility in patients with unilateral pulmonary branch stenosis remains unclear. We present a case involving a 17-year-old patient with left pulmonary branch stenosis who exhibited exercise-induced PH in the contralateral pulmonary artery as detected by ESE. Standard echocardiography was unable to visualize the left pulmonary artery clearly; therefore, computed tomography was performed, revealing a left pulmonary branch stenosis with a minimum diameter of 4.2 mm. Resting echocardiography showed a pressure gradient of 17 mmHg, calculated using the tricuspid regurgitant velocity. During ESE with a prone ergometer, the slope of the mean pulmonary arterial pressure to systemic cardiac output was 3.1 mmHg/L/min, meeting the diagnostic criteria for exercise-induced PH. The patient underwent stent implantation to treat the left pulmonary branch stenosis. Follow-up ESE demonstrated improvement, with the slope of the mean pulmonary arterial pressure to systemic cardiac output decreasing to 1.5 mmHg/L/min. These findings underscore that ESE is both feasible and effective for assessing subclinical unilateral pulmonary branch stenosis. Learning objective: Patients with congenital unilateral peripheral branch pulmonary artery stenosis usually do not have pulmonary hypertension at rest, and identifying patients who require treatment is challenging. Exercise stress echocardiography can detect latent pulmonary hypertension of the contralateral pulmonary artery in some patients, providing valuable insights for determining treatment indications and evaluating the efficacy of catheter interventions for the stenotic lesion.
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Takahashi H., Tanaka S., Yuza Y., Iijima-Yamashita Y., Hasegawa D., Moritake H., Terui K., Iwamoto S., Shimada A., Matsubayashi J., Deguchi T., Hashii Y., Kiyokawa N., Miyachi H., Saito A.M., Taga T., Adachi S., Tomizawa D.
International Journal of Hematology 2025
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Hematology
Arsenic trioxide (ATO) in combination with all-trans retinoic acid (ATRA) has been shown to be effective in both adult and pediatric patients with acute promyelocytic leukemia (APL). Addition of ATO to conventional chemotherapy could lead to a reduction in the doses of cytotoxic agents, but the long-term safety of ATO is not fully understood, especially in children. The Japan Children’s Cancer Group conducted a risk-stratified prospective study to investigate safety and efficacy of ATO in children with newly diagnosed APL by replacing all three intensification phases with ATO. The 3-year event-free survival and overall survival rates in 27 children were 96.3% (95% CI 76.5%–99.5%) and 100% (95% CI 87.2%–100%), respectively. Prolonged QTc interval or other cardiac conduction disorders of any grade were observed in 20 out of the 63 intensification cycles. The durations of leukocytopenia, neutropenia, and G-CSF treatment were significantly shorter in this study than in a previous Japanese study that used conventional cytotoxic chemotherapy. Furthermore, no cardiac, metabolic, renal, cutaneous, or neurological symptoms were reported for up to 5 years after completion of the protocol therapy. The JPLSG AML-P13 study demonstrated excellent outcomes and safety of ATO in children with APL.
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Severe sinusoidal obstruction syndrome successfully treated with extracorporeal ultrafiltration method Reviewed
Wakamatsu Fumito, Kurogi Jun, Ebihara Shusei, Sakaguchi Hiromi, Nagasawa Shun, Nakagawa Midori, Yamada Ai, Tanaka Etsuko, Kinoshita Mariko, Konomoto Takao, Moritake Hiroshi
Japanese journal of pediatric nephrology 38 ( 0 ) n/a 2025
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：The Japanese Society for Pediatric Nephrology
Sinusoidal obstruction syndrome (SOS) is a serious complication of hematopoietic stem cell transplantation, characterized by diuretic-resistant edema and weight gain. Severe cases can progress to multiple organ failure due to abdominal compartment syndrome, and the mortality rate remains high even with defibrotide, a known effective treatment for SOS.We present a case of severe SOS in a patient who was treated with extracorporeal ultrafiltration (ECUM) as part of continuous renal replacement therapy (CRRT). The patient received defibrotide immediately upon diagnosis of SOS following peripheral hematopoietic stem cell transplantation; however, he subsequently developed severe ascites and respiratory distress. Initiation of ECUM led to rapid improvement in fluid overload, including ascites, along with increased urine output. The patient was successfully weaned off ECUM within a short period, and his SOS symptoms improved. This case suggests that ECUM may effectively alleviate ascites related to SOS.Effective management of fluid overload is critical in the treatment of SOS. Regardless of renal function, close monitoring of fluid volume using percentage fluid overload (%FO) is essential, and CRRT should be initiated promptly based on the patient’s clinical status. ECUM may serve as an effective treatment option for managing SOS-related fluid overload.
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Re-evaluating the MYH9 p.I1816V variant in a patient with atypical clinical presentation Reviewed
Konomoto T., Wakamatsu F., Sakaguchi H., Kurogi J., Tanaka E., Moritake H.
Pediatric Nephrology 2025
Language：English Publishing type：Research paper (scientific journal) Publisher：Pediatric Nephrology
MYH9-related disease (MYH9-RD) is an autosomal dominant disorder typically characterized by macrothrombocytopenia, leukocyte inclusion bodies, and variable non-hematologic manifestations such as hearing loss and nephropathy. We herein describe a 16-year-old boy presenting with persistent proteinuria and biopsy-proven membranous nephropathy with focal segmental sclerosis. Genetic testing identified a rare MYH9 variant (p.I1816V), previously reported in association with Epstein syndrome. However, the patient had normal platelet counts, no leukocyte inclusions, and no abnormalities in non-muscle myosin heavy chain IIA (NMMHC-IIA) expression in neutrophils or podocytes. Although globally rare, the p.I1816V variant is more frequent in East Asian populations and is predicted to be benign by multiple in silico tools. This case illustrates the challenges of interpreting rare variants in the absence of supportive clinical findings and highlights the need for cautious evaluation in the era of next-generation sequencing.
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Goto H., Suenobu S., Koga Y., Yamamoto S., Nakashima K., Oba U., Hasegawa D., Usami I., Yamamori A., Moritake H., Nobusawa S., Okuno K., Kawaguchi K., Kanno M., Ishida H., Cho Y., Nishida H., Tomizawa D., Ihara K., Ohga S.
Frontiers in Hematology 4 2025
Publishing type：Research paper (scientific journal) Publisher：Frontiers in Hematology
Background: Epigenetic dysregulation plays a central role in pediatric acute myeloid leukemia (AML), yet its clinical relevance remains underexplored. This study primarily aimed to elucidate the clinical effect of H3K27me3 and H3K4me3 status on pediatric acute myeloid leukemia. We evaluated the prognostic impact of H3K27me3 and H3K4me3 histone trimethylation, along with associated gene expression profiles, in pediatric AML. Methods: We retrospectively analyzed 74 children with newly diagnosed non-FAB M3 and non-Down syndrome AML in a prolonged cohort in Japan. Bone marrow immunohistochemistry assessed H3K27me3 and H3K4me3 expression levels. RNA sequencing was successfully performed on sorted leukemic blasts in six representative cases, owing to limited sample availability. Chemoresistance and epigenetic modulation were evaluated in AML cell lines treated with GSK-J4, a histone demethylase inhibitor. Results: High H3K27me3 expression at diagnosis was significantly associated with superior overall and event-free survival over three years (OS HR 8.0; EFS HR 5.0; both p < 0.01). H3K4me3 levels at diagnosis showed no prognostic impact. Among 14 KMT2A-rearranged cases, all six patients with high H3K27me3 achieved a long-term first remission (median follow-up: 10 years), whereas those with low expression had higher relapse rates. Transcriptomic analysis revealed upregulation of HOXA9, and HOXA-cluster genes and downregulation of ABCB1, in low H3K27me3 samples. In vitro, GSK-J4 increased H3K27me3 and suppressed HOXA9 expression in KG-1 cells, enhancing sensitivity to cytarabine. Conclusion: Low H3K27me3 expression defines a poor-risk group in pediatric AML, potentially via HOXA9-driven dysregulation. H3K27me3 may serve as a prognostic biomarker and potential therapeutic target.
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CFAP43 variant in persistent respiratory symptoms after hematopoietic cell transplantation Reviewed
Nagasawa S., Nishimura T., Yamada A., Kamimura S., Ishimura M., Moritake H.
Human Genome Variation 11 ( 1 ) 41 2024.12
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Human Genome Variation
We describe a case of RAS-associated autoimmune leukoproliferative disease with primary ciliary dyskinesia (PCD)-like symptoms, such as recurrent pneumonia, sinusitis, and otitis media, that occurred 7 years after hematopoietic cell transplantation. Whole-exome sequencing revealed a heterozygous CFAP43 nonsense variant. Environmental factors related to hematopoietic cell transplantation may have led to PCD symptoms in this patient with this variant. Genetic screening can help avoid subsequent complications during patient management.
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Mitochondrial dynamics as a potential therapeutic target in acute myeloid leukemia Reviewed
Kinoshita M., Saito Y., Otani K., Uehara Y., Nagasawa S., Nakagawa M., Yamada A., Kamimura S., Moritake H.
International Journal of Hematology 120 ( 5 ) 601 - 612 2024.11
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Hematology
Acute myeloid leukemia (AML) cells are highly dependent on oxidative phosphorylation and the mitochondrial dynamics regulated by fusion-related genes MFN1, MFN2, and OPA1 and fission-related genes DNM1L and MFF. An analysis of previously published gene expression datasets showed that high expression of MFF was significantly associated with poor prognosis in patients with AML. Based on this finding, we investigated the impact of mitochondrial dynamics in AML. Transduction of shRNA against fission-related genes, DNM1L and MFF, inhibited growth and increased the mitochondrial area in AML cell lines. Extracellular flux analysis showed that deletion of mitochondrial dynamic regulators reduced mitochondrial respiration without significantly affecting glycolysis, except in shDNM1L-transfected cells. Immunodeficient NOG mice transplanted with DNM1L- or MFF-knockdown AML cells survived significantly longer than controls. Treatment of AML cell lines with Mdivi-1, which inhibits the DRP1 encoded by DNM1L, inhibited cell proliferation and oxidative phosphorylation. Our results show that mitochondrial dynamics play an important role in AML, and provide novel biological insights. The inhibition of mitochondrial dynamics induces unique mitochondrial alterations, which may be explored as a potential therapeutic target in AML.
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HDAC Inhibitors Induce HLA Class I Molecules through the SOX10–IRF1 Axis in Clear Cell Sarcoma Cells Reviewed
Nguyen Minh Thi, Kikuchi Ryota, Nishibu Soshi, Zhou Yue, Moritake Hiroshi, Nakamura Takuro, Outani Hidetatsu, Hayashi Ryuji, Sakurai Hiroaki, Yokoyama Satoru
Biological and Pharmaceutical Bulletin 47 ( 11 ) 1913 - 1919 2024.11
Language：English Publishing type：Research paper (scientific journal) Publisher：The Pharmaceutical Society of Japan
Although immune checkpoint inhibitors (ICIs) are an effective treatment for clear cell sarcoma (CCS), a rare melanocytic sarcoma with a poor prognosis, their efficacies are still limited. Therefore, a novel therapeutic strategy is required to improve the efficacy of ICIs. We previously reported that histone deacetylase (HDAC) inhibitors increased melanoma immunogenicity through the SOX10–IRF1 pathway and may improve the efficacy of ICIs for melanoma. We herein demonstrated that the inhibition of HDAC induced the expression of HLA class I molecules through IRF1 in CCS cells, similar to melanoma. The suppression of SOX10 by small interfering RNA (siRNA) induced the expression of HLA class I molecules. In addition, the isoform-specific inhibition of HDAC1/3 induced the expression of another IRF1 downstream molecule, PD-L1 in CCS cells in concert with the suppression of SOX10. Furthermore, the knockdown of IRF1 impaired the induction of PD-L1 expression in CCS cells. Therefore, the inhibition of HDAC1/3 has potential as a novel strategy to increase immunogenicity and as combination therapy with ICIs for CCS and melanoma.
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Isolated Blind-Ended Major Aortic Pulmonary Collateral Artery With an Aneurysm in an Infant With Trisomy 21. Reviewed
Yonaga R, Kodama Y, Takamura K, Harada M, Moritake H
Cureus 16 ( 10 ) e72078 2024.10
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)
DOI： 10.7759/cureus.72078
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Kato S, Nakashima K, Yamato G, Saito S, Taneyama Y, Yamamoto N, Miyamura T, Kato K, Sato Y, Yamada A, Kamiya T, Nishikawa T, Uemura S, Tomizawa D, Moritake H, Terui K, Taga T, Hasegawa D
Pediatric blood & cancer 71 ( 10 ) e31244 2024.8
Language：English Publishing type：Research paper (scientific journal) Publisher：Pediatric Blood and Cancer
Hypomethylating agent treatment for myeloid leukemia associated with Down syndrome (ML-DS) has been scarcely reported. Herein, we collected information on azacitidine treatment for ML-DS in Japan. Forty-eight cycles of azacitidine treatment were performed for 12 patients, including 11 relapsed or refractory (R/R) patients. In 40 cycles, azacitidine was used as monotherapy. No azacitidine-related death was observed. One cycle concurrently administered with methotrexate-based intrathecal therapy was discontinued due to toxicities. Only 4 of the 19 cycles given in non-remission achieved complete or partial remission. In conclusion, although most toxicities were acceptable, azacitidine monotherapy might be insufficient for R/R ML-DS cases.
DOI： 10.1002/pbc.31244