Faculty Profiles - MURAMATSU, Hideki

Correction: Reduced-intensity conditioning is effective for hematopoietic stem cell transplantation in young pediatric patients with Diamond-Blackfan anemia (Bone Marrow Transplantation, (2021), 56, 5, (1013-1020), 10.1038/s41409-020-01056-1) Reviewed

Successful treatment of a novel type I interferonopathy due to a de novo PSMB9 gene mutation with a Janus kinase inhibitor Reviewed Open Access

Kataoka S., Kawashima N., Okuno Y., Muramatsu H., Miwata S., Narita K., Hamada M., Murakami N., Taniguchi R., Ichikawa D., Kitazawa H., Suzuki K., Nishikawa E., Narita A., Nishio N., Yamamoto H., Fukasawa Y., Kato T., Yamamoto H., Natsume J., Kojima S., Nishino I., Taketani T., Ohnishi H., Takahashi Y.

Journal of Allergy and Clinical Immunology Vol. 148 ( 2 ) page： 639 - 644 2021.8

Language：Japanese Publisher：Journal of Allergy and Clinical Immunology

Background: Type I interferonopathies are a recently established subgroup of autoinflammatory diseases caused by mutations in genes associated with proteasome degradation or cytoplasmic RNA- and DNA-sensing pathways. Objective: This study aimed to unveil the molecular pathogenesis of a patient with novel type I interferonopathy, for which no known genetic mutations have been identified. Methods: We performed the whole-exome sequencing of a 1-month-old boy with novel type I interferonopathy. We also investigated proteasome activities using patient-derived B lymphoblastoid cell lines (LCLs) and normal LCLs transduced with the mutant gene. Results: Whole-exome sequencing identified a de novo proteasome 20S subunit beta 9 (PSMB9) p.G156D mutation in the patient who developed fever, a chilblain-like skin rash, myositis, and severe pulmonary hypertension due to the hyperactivation of IFN-α. Patient-derived LCLs revealed reduced proteasome activities, and exogenous transduction of mutant PSMB9 p.G156D into normal LCLs significantly suppressed proteasome activities, and the endogenous PSMB9 protein was lost along with the reduction of other immunoproteasome subunits, PSMB8 and PSMB10 proteins. He responded to the administration of a Janus kinase inhibitor, tofacitinib, and he was successfully withdrawn from venoarterial extracorporeal membranous oxygenation. At age 7 months, he received an unrelated cord blood transplantation. At 2 years posttransplantation, he no longer required tofacitinib and experienced no disease recurrence. Conclusions: We present the case of a patient with a novel type I interferonopathy caused by a de novo PSMB9 p.G156D mutation that suppressed the wild-type PSMB9 protein expression. Janus kinase inhibitor and stem cell transplantation could be curative therapies in patients with severe interferonopathies.

DOI： 10.1016/j.jaci.2021.03.010

Shun Koyamaishi, Takuya Kamio, Akie Kobayashi, Tomohiko Sato, Ko Kudo, Shinya Sasaki, Rika Kanezaki, Daiichiro Hasegawa, Hideki Muramatsu, Yoshiyuki Takahashi, Yoji Sasahara, Hidefumi Hiramatsu, Harumi Kakuda, Miyuki Tanaka, Masataka Ishimura, Masanori Nishi, Akira Ishiguro, Hiromasa Yabe, Takeo Sarashina, Masaki Yamamoto, Yuki Yuza, Nobuyuki Hyakuna, Kenichi Yoshida, Hitoshi Kanno, Shouichi Ohga, Akira Ohara, Seiji Kojima, Satoru Miyano, Seishi Ogawa, Tsutomu Toki, Kiminori Terui, Etsuro Ito

Bone Marrow Transplantation Vol. 56 ( 5 ) page： 1218 - 1219 2021.5

Reduced-intensity conditioning is effective for hematopoietic stem cell transplantation in young pediatric patients with Diamond–Blackfan anemia Reviewed

Koyamaishi S., Kamio T., Kobayashi A., Sato T., Kudo K., Sasaki S., Kanezaki R., Hasegawa D., Muramatsu H., Takahashi Y., Sasahara Y., Hiramatsu H., Kakuda H., Tanaka M., Ishimura M., Nishi M., Ishiguro A., Yabe H., Sarashina T., Yamamoto M., Yuza Y., Hyakuna N., Yoshida K., Kanno H., Ohga S., Ohara A., Kojima S., Miyano S., Ogawa S., Toki T., Terui K., Ito E.

Bone Marrow Transplantation Vol. 56 ( 5 ) page： 1013 - 1020 2021.5

Language：Japanese Publisher：Bone Marrow Transplantation

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for the hematologic manifestations of Diamond–Blackfan anemia (DBA). However, data regarding the optimal conditioning regimen for DBA patients are limited. We retrospectively compared the outcomes of DBA patients who underwent HSCT using either myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC) regimens. The patients belonged to a cohort treated at our hospitals between 2000 and 2018. HSCT was performed in 27 of 165 patients (16.4%). The median age at the time of HSCT was 3.6 years. Stem cell sources included bone marrow for 25 patients (HLA-matched sibling donors, n = 5; HLA-mismatched related donors, n = 2; HLA-matched/mismatched unrelated donors, n = 18) or cord blood for 2 patients. MAC or RIC regimens were used in 12 and 15 patients, respectively. Engraftment was successful in all 27 patients who underwent HSCT. Three patients who underwent HSCT using MAC regimens developed sinusoidal obstruction syndrome. The 3-year overall survival (OS) and failure-free survival rates (FFS) post-transplantations were 95.2% and 88.4%, respectively, with no significant differences between MAC and RIC regimens. Our data suggest that HSCTs using RIC regimens are effective and obtain engraftment with excellent OS and FFS for young DBA patients.

DOI： 10.1038/s41409-020-01056-1

Predictive factors for the development of leukemia in patients with transient abnormal myelopoiesis and Down syndrome Reviewed

Yamato G., Deguchi T., Terui K., Toki T., Watanabe T., Imaizumi T., Hama A., Iwamoto S., Hasegawa D., Ueda T., Yokosuka T., Tanaka S., Yanagisawa R., Koh K., Saito A.M., Horibe K., Hayashi Y., Adachi S., Mizutani S., Taga T., Ito E., Watanabe K., Muramatsu H.

Leukemia Vol. 35 ( 5 ) page： 1480 - 1484 2021.5

The eldest case of MICPCH with CASK mutation exhibiting gross motor regression Reviewed

Nishio Y., Kidokoro H., Takeo T., Narita H., Sawamura F., Narita K., Kawano Y., Nakata T., Muramatsu H., Hara S., Kaname T., Natsume J.

Brain and Development Vol. 43 ( 3 ) page： 459 - 463 2021.3

Language：Japanese Publisher：Brain and Development

Background: MICPCH is manifested as microcephaly associated with pontocerebellar hypoplasia and global developmental delay but developmental regression has never been reported. We describe the detailed clinical history of a woman with intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH) with a CASK mutation who exhibited gross motor regression after adolescence. Case: The patient experienced severe motor and intellectual developmental delay with microcephaly from infancy. The initial diagnosis was Rett syndrome based on her clinical features, including hand stereotypes and the absence of structural abnormality on magnetic resonance imaging (MRI) performed at the age of 5 years. Although gross motor abilities developed slowly and she could walk independently, she never acquired speech or understanding of languages. After adolescence, her motor ability gradually regressed so that she was unable to stand without support and moved with a wheelchair. At the age of 31 years, because of her atypical clinical course for Rett syndrome, whole exome sequencing was performed, which revealed a de novo heterozygous c.2068 + 1G > A mutation in the CASK gene (NM_001126055). Brain MRI revealed mild pontocerebellar hypoplasia compatible with the clinical phenotype of MICPCH. Discussion: This case suggests that MICPCH with a CASK mutation might cause developmental regression after adolescence and might be regarded as a neurodegenerative disorder.

DOI： 10.1016/j.braindev.2020.11.007

International consensus definition of DNA methylation subgroups in juvenile myelomonocytic leukemia Reviewed

Schonung M., Meyer J., Nollke P., Olshen A.B., Hartmann M., Murakami N., Wakamatsu M., Okuno Y., Plass C., Loh M.L., Niemeyer C.M., Muramatsu H., Flotho C., Stieglitz E., Lipka D.B.

Clinical Cancer Research Vol. 27 ( 1 ) page： 158 - 168 2021.1

Language：Japanese Publisher：Clinical Cancer Research

Purpose: Known clinical and genetic markers have limitations in predicting disease course and outcome in juvenile myelomonocytic leukemia (JMML). DNA methylation patterns in JMML have correlated with outcome across multiple studies, suggesting it as a biomarker to improve patient stratification. However, standardized approaches to classify JMML on the basis of DNA methylation patterns are lacking. We, therefore, sought to define an international consensus for DNA methylation subgroups in JMML and develop classification methods for clinical implementation. Experimental Design: Published DNA methylation data from 255 patients with JMML were used to develop and internally validate a classifier model. Accuracy across platforms (EPIC-arrays and MethylSeq) was tested using a technical validation cohort (32 patients). The suitability of both methods for single-patient classification was demonstrated using an independent cohort (47 patients). Results: Analysis of pooled, published data established three DNA methylation subgroups as a de facto standard. Unfavorable prognostic parameters (PTPN11 mutation, elevated fetal hemoglobin, and older age) were significantly enriched in the high methylation (HM) subgroup. A classifier was then developed that predicted subgroups with 98% accuracy across different technological platforms. Applying the classifier to an independent validation cohort confirmed an association of HM with secondary mutations, high relapse incidence, and inferior overall survival (OS), while the low methylation subgroup was associated with a favorable disease course. Multivariable analysis established DNA methylation subgroups as the only significant factor predicting OS. Conclusions: This study provides an international consensus definition for DNA methylation subgroups in JMML. We developed and validated methods which will facilitate the design of risk-stratified clinical trials in JMML.

DOI： 10.1158/1078-0432.CCR-20-3184

Detection of subclonal SETBP1 and JAK3 mutations in juvenile myelomonocytic leukemia using droplet digital PCR Reviewed

Wakamatsu M., Okuno Y., Murakami N., Miwata S., Kitazawa H., Narita K., Kataoka S., Ichikawa D., Hamada M., Taniguchi R., Suzuki K., Kawashima N., Nishikawa E., Narita A., Nishio N., Kojima S., Muramatsu H., Takahashi Y.

Leukemia Vol. 35 ( 1 ) page： 259 - 263 2021.1

Usefulness of functional splicing analysis to confirm precise disease pathogenesis in Diamond-Blackfan anemia caused by intronic variants in RPS19 Reviewed

Takafuji S., Mori T., Nishimura N., Yamamoto N., Uemura S., Nozu K., Terui K., Toki T., Ito E., Muramatsu H., Takahashi Y., Matsuo M., Yamamura T., Iijima K.

Pediatric Hematology and Oncology Vol. 38 ( 6 ) page： 515 - 527 2021

Language：Japanese Publisher：Pediatric Hematology and Oncology

Diamond-Blackfan anemia (DBA) is mainly caused by pathogenic variants in ribosomal proteins and 22 responsible genes have been identified to date. The most common causative gene of DBA is RPS19 [NM_001022.4]. Nearly 180 RPS19 variants have been reported, including three deep intronic variants outside the splicing consensus sequence (c.72-92A > G, c.356 + 18G > C, and c.411 + 6G > C). We also identified one case with a c.412-3C > G intronic variant. Without conducting transcript analysis, the pathogenicity of these variants is unknown. However, it is difficult to assess transcripts because of their fragility. In such cases, in vitro functional splicing assays can be used to assess pathogenicity. Here, we report functional splicing analysis results of four RPS19 deep intronic variants identified in our case and in previously reported cases. One splicing consensus variant (c.411 + 1G > A) was also examined as a positive control. Aberrant splicing with a 2-bp insertion between exons 5 and 6 was identified in the patient samples and minigene assay results also identified exon 6 skipping in our case. The exon 6 skipping transcript was confirmed by further evaluation using quantitative RT-PCR. Additionally, minigene assay analysis of three reported deep intronic variants revealed that none of them showed aberrant splicing and that these variants were not considered to be pathogenic. In conclusion, the minigene assay is a useful method for functional splicing analysis of inherited disease.

DOI： 10.1080/08880018.2021.1887984

Two Aldehyde Clearance Systems Are Essential to Prevent Lethal Formaldehyde Accumulation in Mice and Humans Reviewed

Dingler F.A., Wang M., Mu A., Millington C.L., Oberbeck N., Watcham S., Pontel L.B., Kamimae-Lanning A.N., Langevin F., Nadler C., Cordell R.L., Monks P.S., Yu R., Wilson N.K., Hira A., Yoshida K., Mori M., Okamoto Y., Okuno Y., Muramatsu H., Shiraishi Y., Kobayashi M., Moriguchi T., Osumi T., Kato M., Miyano S., Ito E., Kojima S., Yabe H., Yabe M., Matsuo K., Ogawa S., Göttgens B., Hodskinson M.R.G., Takata M., Patel K.J.

Molecular Cell Vol. 80 ( 6 ) page： 996 - 1012.e9 2020.12

Language：Japanese Publisher：Molecular Cell

Dingler et al. show that formaldehyde is produced endogenously at sufficient levels to induce and overwhelm DNA repair. Two enzymes, ADH5 and ALDH2, are critical in clearance of formaldehyde, whose loss results in a bone marrow failure and leukemia syndrome of purely metabolic origin.

DOI： 10.1016/j.molcel.2020.10.012

Digenic mutations in ALDH2 and ADH5 impair formaldehyde clearance and cause a multisystem disorder, AMeD syndrome Reviewed

Oka Y., Hamada M., Nakazawa Y., Muramatsu H., Okuno Y., Higasa K., Shimada M., Takeshima H., Hanada K., Hirano T., Kawakita T., Sakaguchi H., Ichimura T., Ozono S., Yuge K., Watanabe Y., Kotani Y., Yamane M., Kasugai Y., Tanaka M., Suganami T., Nakada S., Mitsutake N., Hara Y., Kato K., Mizuno S., Miyake N., Kawai Y., Tokunaga K., Nagasaki M., Kito S., Isoyama K., Onodera M., Kaneko H., Matsumoto N., Matsuda F., Matsuo K., Takahashi Y., Mashimo T., Kojima S., Ogi T.

Science Advances Vol. 6 ( 51 ) 2020.12

Language：Japanese Publisher：Science Advances

Rs671 in the aldehyde dehydrogenase 2 gene (ALDH2) is the cause of Asian alcohol flushing response after drinking. ALDH2 detoxifies endogenous aldehydes, which are the major source of DNA damage repaired by the Fanconi anemia pathway. Here, we show that the rs671 defective allele in combination with mutations in the alcohol dehydrogenase 5 gene, which encodes formaldehyde dehydrogenase (ADH5FDH), causes a previously unidentified disorder, AMeD (aplastic anemia, mental retardation, and dwarfism) syndrome. Cellular studies revealed that a decrease in the formaldehyde tolerance underlies a loss of differentiation and proliferation capacity of hematopoietic stem cells. Moreover, Adh5−/−Aldh2E506K/E506K double-deficient mice recapitulated key clinical features of AMeDS, showing short life span, dwarfism, and hematopoietic failure. Collectively, our results suggest that the combined deficiency of formaldehyde clearance mechanisms leads to the complex clinical features due to overload of formaldehyde-induced DNA damage, thereby saturation of DNA repair processes.

DOI： 10.1126/SCIADV.ABD7197

Microsatellite Instability-High is Rare Events in Refractory Pediatric Solid Tumors Reviewed

Yoshida, T; Muramatsu, H; Wakamatsu, M; Taniguchi, R; Ichikawa, D; Nakaguro, M; Natsume, A; Takahashi, Y

PEDIATRIC BLOOD & CANCER Vol. 67 2020.12

Myelodysplastic syndromes in a pediatric patient with Cri du Chat syndrome with a ring chromosome 5 Reviewed

Nozawa A., Ozeki M., Yasue S., Endo S., Kadowaki T., Ohnishi H., Muramatsu H., Hama A., Takahashi Y., Kojima S., Fukao T.

International Journal of Hematology Vol. 112 ( 5 ) page： 728 - 733 2020.11

Language：Japanese Publisher：International Journal of Hematology

Few hematological complications have previously been reported in association with Cri du Chat syndrome (CdCS). A case of myelodysplastic syndromes (MDS) in a pediatric patient with CdCS is herein presented. A 17-year-old female with CdCS caused by ring chromosome 5 was admitted to the hospital for investigation of a 1-month history of anemia. Based on the morphological findings of bone marrow, the patient was diagnosed with refractory cytopenia with multilineage dysplasia. The risk group was classified as intermediate-1 in the International Prognostic Scoring System (IPSS), and low in the revised IPSS. Assessment by microarray comparative genomic hybridization (CGH) identified the breakpoints of ring chromosome 5 as 46,XX,r(5)(p14.3q35.3). This revealed that the 5q terminal deletion did not include the common deleted region of MDS with del(5q). Treatment with azacitidine was initiated to control disease progression and improve quality of life. At baseline, the patient had a mean transfusion requirement of 3 units/month, which decreased to 2 units/month after six cycles of azacitidine and to 1 unit/month after 10 cycles of azacitidine. Cytopenia observed in the presented case seemed irrelevant to ring chromosome 5 which is the causative cytogenetic abnormality of CdCS, and further analyses may be needed to clarify the pathogenesis.

DOI： 10.1007/s12185-020-02909-7

Risk factors for secondary poor graft function after bone marrow transplantation in children with acquired aplastic anemia Reviewed

Hama A., Muramatsu H., Narita A., Nishikawa E., Kawashima N., Nishio N., Kojima S., Takahashi Y.

Pediatric Transplantation Vol. 24 ( 7 ) page： e13828 2020.11

Language：Japanese Publisher：Pediatric Transplantation

In patients with acquired AA, PGF is a major cause of cytopenia after hematopoietic stem cell transplantation. An increased incidence of PGF, especially sPGF, has been noted after the introduction of the FLU/CY regimen in children with acquired AA. To clarify the risk factors for sPGF, the clinical data of 49 patients (median age, 11 years; range, 1-19 years) with AA who received allogeneic BMT at Nagoya University Hospital from 1997 to 2016 were analyzed. Out of the 49 patients, 7 developed sPGF, and the 5-year CI was 0.15 (95% CI, 0.04-0.25). Five received the FLU/CY regimen, and the 5-year CI of sPGF was significantly higher in patients who received the regimen (0.36; 95% CI, 0.12-0.62) than in those who were conditioned with the non-FLU/CY regimen (0.06; 95% CI, 0.01-0.17; P =.01). The multivariate analysis confirmed that the FLU/CY regimen (hazard ratio, 6.12; 95% CI, 1.16-32.4; P =.03) was a significant risk factor for sPGF. sPGF improved spontaneously without stem cell boost infusions in 5 patients, ranging from 460 to 3539 days after BMT. The 10-year CI of the spontaneous trilineage recovery was 0.83 (95% CI, 0.00-0.97), and all 7 patients are alive. The FLU/CY regimen was identified as a risk factor for the sPGF development in patients with AA. The establishment of the optimal conditioning regimens for children with AA is warranted.

DOI： 10.1111/petr.13828

MicroRNA-155-5p plays a critical role in transient leukemia of down syndrome by targeting tumor necrosis factor receptor superfamily members Reviewed

Sas V., Pasca S., Jurj A., Pop L., Muramatsu H., Ono H., Dima D., Teodorescu P., Iluta S., Turcas C., Onaciu A., Munteanu R., Zimta A.A., Blag C., Popa G., von Gamm E.D.A., Arghirescu S., Serban M., Man S., Marian M., Petrushev B., Berce C., Colita A., Zdrenghea M., Kojima S., Gulei D., Takahashi Y., Tomuleasa C.

Cellular Physiology and Biochemistry Vol. 54 ( 5 ) page： 994 - 1012 2020.10

Language：Japanese Publisher：Cellular Physiology and Biochemistry

Background/Aims: Down syndrome associated disorders are caused by a complex genetic context where trisomy 21 is a central component in relation to other changes involving epigenetic regulators and signaling molecules. This unique genetic context is responsible for the predisposition of people with Down syndrome to acute leukemia. Although, the research in this field has discovered some important pathogenic keys, the exact mechanism of this predisposition is not known. Methods: In this study we applied functional enrichment analysis to evaluate the interactions between genes localized on chromosome 21, genes already identify as having a key role in acute leukemia of Down syndrome, miRNAs and signaling pathways implicated in cancer and cell development and found that miR-155 has a high impact in genes present on chromosome 21. Forward, we performed next generation sequencing on DNA samples from a cohort of patients diagnosed with acute leukemia of Down syndrome and in vitro functional assay using a CMK-86 cell line, transfected with either mimic or inhibitor of the microRNA-155-5p. Results: Our results show that the epigenetic alteration of the TNF superfamily receptors in Down syndrome, which can be correlated to microRNA-155-5p aberrant activity, may play an important role in cell signaling and thus be linked to acute myeloid leukemia. Conclusion: Some genes, already shown to be mutated in AML-DS, are potential targets for miR-155. Our results show that the epigenetic alteration of the TNF superfamily receptors in Down syndrome may play an important role in cell signaling and thus be linked to acute myeloid leukemia.

DOI： 10.33594/000000283

Change of White Matter Integrity in Children With Hematopoietic Stem Cell Transplantation Reviewed

Sakaguchi Y., Natsume J., Kidokoro H., Tanaka M., Okai Y., Ito Y., Yamamoto H., Ohno A., Nakata T., Nakane T., Kawai H., Taoka T., Muramatsu H., Naganawa S., Takahashi Y.

Pediatric Neurology Vol. 111 page： 78 - 84 2020.10

Language：Japanese Publisher：Pediatric Neurology

Background: Advances in hematopoietic stem cell transplantation have improved the survival rate of malignant diseases and congenital immunodeficiencies. It has become important to assess long-term complications in survivors. To assess neurological abnormalities in children treated by transplantation, diffusion tensor imaging was performed. Methods: Forty children who underwent head diffusion tensor imaging before and after their first transplantation were enrolled. Patients with brain lesions on conventional MRI were excluded. Fractional anisotropy and mean diffusivity were compared between patients and 28 control subjects using tract-based spatial statistics. The Strengths and Difficulties Questionnaire was administered as a behavioral evaluation after transplantation, and diffusion tensor images of patients with and without behavioral abnormalities were compared. Results: The age of patients and controls was 0 to 19 years and 0 to 16 years, respectively. The date of diffusion tensor imaging was 10 to 57 days before and 40 to 153 days after transplantation. Tract-based spatial statistics showed fractional anisotropy reduction in widespread white matter in patients before and after transplantation. Mean diffusivity was high before transplantation and normalized after transplantation. Analysis comparing before and after hematopoietic stem cell transplantation shows no difference in fractional anisotropy and significantly high mean diffusivity before hematopoietic stem cell transplantation. In patients with behavioral abnormalities, low fractional anisotropy and high mean diffusivity remained after transplantation. Conclusions: Longitudinal diffusion tensor imaging showed white matter abnormalities in children without conventional MRI abnormalities, which were related to behavioral problems after transplantation. Diffusion tensor imaging is useful for behavioral assessment in children undergoing transplantation.

DOI： 10.1016/j.pediatrneurol.2020.06.008