Authorship：Lead author,　Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1182/blood.2025030209

PubMed

Authorship：Lead author,　Last author,　Corresponding author   Language：English   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.

DOI： 10.3389/frhem.2025.1668408

Web of Science

Scopus

Language：English   Publisher：Pediatric Blood and Cancer  

Programs allowing access to investigational drugs and off-label drug use for serious diseases have often been applied to pediatric cancers. A clinical study conducted under the Japanese “Patient-Proposed Healthcare Services” evaluated the efficacy and safety of dabrafenib plus trametinib in children with BRAF V600 mutant glioma (jRCTs071210071). This study successfully provided unapproved and off-label medications to four enrolled patients, two with low-grade glioma and two with high-grade glioma (median age: 10.5 years), until regulatory approval. The timeframe and data collection from such access programs need to be optimized for pediatric patients in accordance with the healthcare system of each nation.

DOI： 10.1002/pbc.31510

Web of Science

Scopus

PubMed

Language：English   Publisher：Early Human Development  

Background: Many studies have indicated an association between maternal occupational exposure to hazardous agents, such as anticancer drugs and ionizing radiation, and an increased risk of adverse pregnancy outcomes, including stillbirths or miscarriages and physical abnormalities in offspring. However, the effects of recent advancements in protective measures to reduce these risks have not been clarified. Aim To investigate the current impact of parental occupational exposure to anticancer drugs and ionizing radiation on stillbirths or miscarriages as well as physical abnormalities under the circumstances of the developed safety protocols. Methods: This cohort study utilized The Japan Environment and Children's Study dataset, which included 96,606 fetuses born between January 2011 and March 2014. This study focused on the association between occupational exposure to these agents during pregnancy and the incidence of stillbirths or miscarriages and physical abnormalities in offspring, employing Poisson regression models for adjusted relative risk. Results: From the study population, 471 cases of stillbirths or miscarriages and 4493 infants with physical abnormalities were identified. Fisher's exact tests indicated no significant differences in fetal loss or physical abnormalities between the exposure groups. A multivariable analysis also found no significant association between maternal exposure to anticancer drugs and ionizing radiation and these adverse outcomes. Conclusion: Under improved safety measures, maternal occupational exposure to anticancer drugs and ionizing radiation does not significantly affect the occurrence of stillbirths or miscarriages and physical abnormalities in offspring. These findings highlight the critical role of current safety practices and indicate lower reproductive risks with proper precautions.

DOI： 10.1016/j.earlhumdev.2025.106195

Web of Science

Scopus

PubMed

Language：English   Publisher：Pediatric Research  

Background: Healthcare workers are often exposed to hazardous agents and are at risk for adverse health consequences that affect not only themselves but also their infants. This study aimed to examine whether such occupational exposure increased the risk of childhood cancer in offspring. Methods: We used the dataset of the Japan Environment and Children’s Study, a nationwide birth cohort involving over 100,000 mother–child pairs. Information was obtained via successive questionnaires that were completed until the child turned 1 year of age. The parents were asked whether they occupationally handled medical agents during pregnancy. Results: A total of 26 infants developed neoplasms: neuroblastoma, leukemia, and brain tumor. The incidence of neuroblastoma was significantly higher in infants whose mothers were exposed to radiation (3/2142: 140.1 per 100,000 population) than in those who were not (12/90,384: 13.3 per 100,000 population). Multivariable regression analyses revealed a close association between maternal irradiation and the development of neuroblastoma (adjusted incident rate ratio: 10.68 [95% confidence interval: 2.98‒38.27]). Conclusions: The present study demonstrated, for the first time, a potential association between maternal occupational exposure and the occurrence of neuroblastoma in offspring. Further studies involving the large pediatric cancer registries are needed to confirm these preliminary results. Impact: Healthcare workers are often exposed to hazardous agents and are at risk for adverse health consequences that affect not only themselves but also their infants. This study examined the association between such occupational exposure and offspring’s cancers that developed until the age of 1 year. Maternal exposure to ionizing radiation was associated with infantile neuroblastoma in offspring. Further studies involving the large pediatric cancer registries are needed to confirm these preliminary results.

DOI： 10.1038/s41390-021-01634-z

Scopus

PubMed

Language：English  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：English  

Language：Japanese   Publisher：日本産婦人科・新生児血液学会  

小児がんの細胞起源は胎児期にあり、職業性曝露を含む妊産婦の様々な環境因子への曝露が影響している可能性が指摘されている。抗がん剤や電離放射線への職業性曝露が、流産などの胎児期のリスクになることが報告されているが、小児がん発症との関連については一定の見解が得られていなかった。今回私たちは、妊娠中の母親の職業性の医療用物質曝露が小児がんのリスクになることを前向きコホートで初めて示した。妊娠中の母親の職業性曝露対策が、こどもの発がん予防に寄与する可能性があると考えられた。(著者抄録)

Language：Japanese   Publisher：(有)科学評論社