Faculty Profiles - MURAMATSU, Hideki

Papers - MURAMATSU, Hideki

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Targeting MEF2D-fusion Oncogenic Transcriptional Circuitries in B-cell Precursor Acute Lymphoblastic Leukemia Reviewed Open Access

Shinobu Tsuzuki, Takahiko Yasuda, Shinya Kojima, Masahito Kawazu, Koshi Akahane, Takeshi Inukai, Masue Imaizumi, Takanobu Morishita, Koichi Miyamura, Toshihide Ueno, Sivasundaram Karnan, Akinobu Ota, Toshinori Hyodo, Hiroyuki Konishi, Masashi Sanada, Hirokazu Nagai, Keizo Horibe, Akihiro Tomita, Kyogo Suzuki, Hideki Muramatsu, Yoshiyuki Takahashi, Yasushi Miyazaki, Itaru Matsumura, Hitoshi Kiyoi, Yoshitaka Hosokawa, Hiroyuki Mano, Fumihiko Hayakawa

Blood Cancer Discovery Vol. 1 ( 1 ) page： 82 - 95 2020.7

Conditioning regimen for allogeneic bone marrow transplantation in children with acquired bone marrow failure: fludarabine/melphalan vs. fludarabine/cyclophosphamide Reviewed

Yoshida N., Takahashi Y., Yabe H., Kobayashi R., Watanabe K., Kudo K., Yabe M., Miyamura T., Koh K., Kawaguchi H., Goto H., Fujita N., Okada K., Okamoto Y., Kato K., Inoue M., Suzuki R., Atsuta Y., Kojima S., Yoshida N., Takahashi Y., Kobayashi R., Watanabe K.i., Kudo K., Kato K., Muramatsu H., Narita A., Wakamatsu M., Kojima S.

Bone Marrow Transplantation Vol. 55 ( 7 ) page： 1272 - 1281 2020.7

Language：Japanese Publisher：Bone Marrow Transplantation

Fludarabine/cyclophosphamide-based conditioning regimens are standard in bone marrow transplantation (BMT) for acquired bone marrow failure in children, however, graft failure may occur. Using the data from a nationwide transplantation registry, we compared the outcomes of children aged <16 years with acquired aplastic anemia and refractory cytopenia of childhood who underwent allogeneic BMT with either fludarabine/melphalan (n = 71) or fludarabine/cyclophosphamide (n = 296) between 2000 and 2016. The fludarabine/melphalan regimen provided excellent outcomes, with 3-year overall survival and failure-free survival rates of 98% and 97%, respectively. The 83% 3-year failure-free survival in the fludarabine/cyclophosphamide group was significantly inferior (P = 0.002), whereas the overall survival did not differ between the two groups. Late graft failure was the most common cause of treatment failure in the fludarabine/cyclophosphamide group, which experienced a significantly higher incidence of late graft failure than the fludarabine/melphalan group (11% vs. 3%; P = 0.035). Multivariate analyses showed that the fludarabine/melphalan regimen was associated with a better failure-free survival (hazard ratio [HR] 0.12; P = 0.005) and lower risk of late graft failure (HR 0.16; P = 0.037). Fludarabine/melphalan-based conditioning regimen can be a promising option for children with acquired bone marrow failure receiving BMT.

DOI： 10.1038/s41409-020-0948-8

Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex Reviewed

Kato K., Oka Y., Muramatsu H., Vasilev F.F., Otomo T., Oishi H., Kawano Y., Kidokoro H., Nakazawa Y., Ogi T., Takahashi Y., Saitoh S.

Journal of Medical Genetics Vol. 57 ( 4 ) page： 245 - 253 2020.4

Language：Japanese Publisher：Journal of Medical Genetics

Background 3C/Ritscher-Schinzel syndrome is characterised by congenital cranio-cerebello-cardiac dysplasia, where CCDC22 and WASHC5 are accepted as the causative genes. In combination with the retromer or retriever complex, these genes play a role in endosomal membrane protein recycling. We aimed to identify the gene abnormality responsible for the pathogenicity in siblings with a 3C/Ritscher-Schinzel-like syndrome, displaying cranio-cerebello-cardiac dysplasia, coloboma, microphthalmia, chondrodysplasia punctata and complicated skeletal malformation. Methods Exome sequencing was performed to identify pathogenic variants. Cellular biological analyses and generation of knockout mice were carried out to elucidate the gene function and pathophysiological significance of the identified variants. Results We identified compound heterozygous pathogenic variants (c.1097dup; p.Cys366Trpfs∗28 and c.2755G>A; p.Ala919Thr) in the VPS35L gene, which encodes a core protein of the retriever complex. The identified missense variant lacked the ability to form the retriever complex, and the frameshift variant induced non-sense-mediated mRNA decay, thereby confirming biallelic loss of function of VPS35L. In addition, VPS35L knockout cells showed decreased autophagic function in nutrient-rich and starvation conditions, as well as following treatment with Torin 1. We also generated Vps35l -/- mice and demonstrated that they were embryonic lethal at an early stage, between E7.5 and E10.5. Conclusions Our results suggest that biallelic loss-of-function variants in VPS35L underlies 3C/Ritscher-Schinzel-like syndrome. Furthermore, VPS35L is necessary for autophagic function and essential for early embryonic development. The data presented here provide a new insight into the critical role of the retriever complex in fetal development.

DOI： 10.1136/jmedgenet-2019-106213

Novel compound heterozygous MCOLN1 mutations identified in a Japanese girl with severe developmental delay and thin corpus callosum Reviewed

Yamaguchi N., Ban K., Suzuki A., Nakamura Y., Kato K., Muramatsu H., Okuno Y., Hattori A., Kaname T., Takahashi Y., Saitoh S.

Brain and Development Vol. 42 ( 3 ) page： 298 - 301 2020.3

Language：Japanese Publisher：Brain and Development

Mucolipidosis type IV (MLIV) is a rare lysosomal storage disorder causing severe psychomotor developmental delay and progressive visual impairment. MLIV is an autosomal recessive disease caused by mutations in MCOLN1, which encodes for mucolipin-1. Here, we report a case of a 4-year-old Japanese girl with severe intellectual disability and motor deficits. Brain magnetic resonance imaging showed signal abnormalities in the white matter and thinning of the corpus callosum. Whole-exome sequencing was performed on the proband and her parents, and novel compound heterozygous mutations at c.936_938del (p.Phe313del) and c.1503dupC (p.Ile502Hisfs*106) in MCOLN1 (NM_020533.2) were identified in the proband. Additional biochemical examinations revealed elevated serum gastrin level and iron deficiency anemia, leading to the diagnosis of MLIV. More reports of such pathogenic mutations are expected to broaden the understanding of the channel function of mucolipin-1 and genotype-phenotype correlations.

DOI： 10.1016/j.braindev.2019.12.003

Novel biallelic FA2H mutations in a Japanese boy with fatty acid hydroxylase-associated neurodegeneration Reviewed

Kawaguchi M., Sassa T., Kidokoro H., Nakata T., Kato K., Muramatsu H., Okuno Y., Yamamoto H., Kaname T., Kihara A., Natsume J.

Brain and Development Vol. 42 ( 2 ) page： 217 - 221 2020.2

Language：Japanese Publisher：Brain and Development

FA2H encodes fatty acid 2-hydroxylase, which plays a significant role in maintaining the neuronal myelin sheath. Previous reports have revealed that a FA2H mutation leads to spastic paraplegia, leukodystrophy, and neurodegeneration with brain iron accumulation, collectively referred to as fatty acid hydroxylase-associated neurodegeneration (FAHN). The disease severity of FAHN varies among individual patients and may be explained by the enzyme activity of FA2H mutant proteins. Here we report a 10-year-old Japanese boy with FAHN having novel heterozygous mutations in FA2H. The patient presented with a spastic gait since the age of 5 years and was unable to walk without a cane by the time he was 8 years old. Brain MRI demonstrated a partial thinning of the corpus callosum, slight reduction of cerebellar volume, and posterior dominant periventricular leukodystrophy. Whole exome sequencing revealed two novel missense mutations in FA2H with compound heterozygous inheritance (NM_024306, p.Val149Leu, and p.His260Gln mutations). The enzyme activities of the p.Val149Leu and p.His260Gln variants were 60%–80% and almost 0%, respectively. Our cell-based enzyme assay demonstrated partial functionality for one of the variants, indicating a milder phenotype. However, considered along with previous reports, there was no definite relationship between the disease severity and residual enzyme activity measured using a similar method. Further research is needed to precisely predict the phenotypic severity of this disorder.

DOI： 10.1016/j.braindev.2019.11.006

Targetable driver mutations in multicentric reticulohistiocytosis Reviewed Open Access

Murakami N., Sakai T., Arai E., Muramatsu H., Ichikawa D., Asai S., Shimoyama Y., Ishiguro N., Takahashi Y., Okuno Y., Nishida Y.

Haematologica Vol. 105 ( 2 ) page： E61 - E64 2020.1

Erratum: Pathogenic mutations identified by a multimodality approach in 117 Japanese Fanconi anemia patients (Haematologica (2019) (1967) DOI: 10.3324/haematol.2018.207241) Reviewed

Mori M., Hira A., Yoshida K., Muramatsu H., Okuno Y., Shiraishi Y., Anmae M., Yasuda J., Tadaka S., Kinoshita K., Osumi T., Noguchi Y., Adachi S., Kobayashi R., Kawabata H., Imai K., Morio T., Tamura K., Takaori-Kondo A., Yamamoto M., Miyano S., Kojima S., Ito E., Ogawa S., Matsuo K., Yabe H., Yabe M., Takata M.

Haematologica Vol. 105 ( 4 ) page： 1166 - 1167 2020

A novel CUL4B splice site variant in a young male exhibiting less pronounced features Reviewed

Nakamura Y., Okuno Y., Muramatsu H., Kawai T., Satou K., Ieda D., Hori I., Ohashi K., Negishi Y., Hattori A., Takahashi Y., Kojima S., Saitoh S.

Human Genome Variation Vol. 6 ( 1 ) page： 43 2019.12

Language：Japanese Publisher：Human Genome Variation

Patients with variants in CUL4B exhibit syndromic intellectual disability (MIM #300354). A seven-year-old boy presented with intellectual disability, a history of seizure, characteristic facial features, and short stature. Whole-exome sequencing detected a c.974+3A>G variant in CUL4B, which was subsequently confirmed to disrupt mRNA splicing. The current patient showed less pronounced phenotypic features compared with the previously reported cases. This report, therefore, provides evidence of genotype–phenotype correlations in CUL4B-related disorders.

DOI： 10.1038/s41439-019-0074-6

Study of pathophysiology and molecular characterization of congenital anemia in India using targeted next-generation sequencing approach Reviewed

Kedar P.S., Harigae H., Ito E., Muramatsu H., Kojima S., Okuno Y., Fujiwara T., Dongerdiye R., Warang P.P., Madkaikar M.R.

International Journal of Hematology Vol. 110 ( 5 ) page： 618 - 626 2019.11

Language：Japanese Publisher：International Journal of Hematology

Most patients with anemia are diagnosed through clinical phenotype and basic laboratory testing. Nonetheless, in cases of rare congenital anemias, some patients remain undiagnosed despite undergoing an exhaustive workup. Genetic testing is complicated by the large number of genes that are involved in rare anemias, due to similarities in the clinical presentation. We sought to enhance the diagnosis of patients with congenital anemias by using targeted next-generation sequencing. The genetic diagnosis was performed by gene capture followed by next-generation sequencing of 76 genes known to cause anemia syndromes. Genetic diagnosis was achieved in 17 of 21 transfusion-dependent patients and undiagnosed by conventional workup. Four cases were diagnosed with red cell membrane protein defects, four patients were diagnosed with pyruvate kinase deficiency, one case of adenylate kinase deficiency, one case of glucose phosphate isomerase deficiency, one case of hereditary xerocytosis, three cases having combined membrane and enzyme defect, two cases with Diamond–Blackfan anemia (DBA) and 1 with CDA type II with 26 different mutations, of which 21 are novel. Earlier incorporation of this NGS method into the workup of patients with congenital anemia may improve patient care and enable genetic counselling.

DOI： 10.1007/s12185-019-02716-9

Essential role of PTPN11 mutation in enhanced haematopoietic differentiation potential of induced pluripotent stem cells of juvenile myelomonocytic leukaemia Reviewed

Shigemura T., Matsuda K., Kurata T., Sakashita K., Okuno Y., Muramatsu H., Yue F., Ebihara Y., Tsuji K., Sasaki K., Nakahata T., Nakazawa Y., Koike K.

British Journal of Haematology Vol. 187 ( 2 ) page： 163 - 173 2019.10

Language：Japanese Publisher：British Journal of Haematology

We established mutated and non-mutated induced pluripotent stem cell (iPSC) clones from a patient with PTPN11 (c.226G>A)-mutated juvenile myelomonocytic leukaemia (JMML). Both types of iPSCs fulfilled the quality criteria. Mutated iPSC colonies generated significantly more CD34+ and CD34+CD45+ cells compared to non-mutated iPSC colonies in a culture coated with irradiated AGM-S3 cells to which four growth factors were added sequentially or simultaneously. The haematopoietic differentiation potential of non-mutated JMML iPSC colonies was similar to or lower than that of iPSC colonies from a healthy individual. The PTPN11 mutation coexisted with the OSBP2 c.389C>T mutation. Zinc-finger nuclease-mediated homologous recombination revealed that correction of PTPN11 mutation in iPSCs with PTPN11 and OSBP2 mutations resulted in reduced CD34+ cell generation to a level similar to that obtained with JMML iPSC colonies with the wild-type of both genes, and interestingly, to that obtained with normal iPSC colonies. Transduction of the PTPN11 mutation into JMML iPSCs with the wild-type of both genes increased CD34+ cell production to a level comparable to that obtained with JMML iPSC colonies harbouring the two genetic mutations. Thus, PTPN11 mutation may be the most essential abnormality to confer an aberrant haematopoietic differentiation potential in this disorder.

DOI： 10.1111/bjh.16060

Prospective randomized trial comparing two doses of rabbit anti-thymocyte globulin in patients with severe aplastic anaemia Reviewed Open Access

Narita A., Zhu X., Muramatsu H., Chen X., Guo Y., Yang W., Zhang J., Liu F., Jang J.H., Kook H., Kim H., Usuki K., Yamazaki H., Takahashi Y., Nakao S., Wook Lee J., Kojima S.

British Journal of Haematology Vol. 187 ( 2 ) page： 227 - 237 2019.10

Language：Japanese Publisher：British Journal of Haematology

The treatment of choice for patients with severe aplastic anaemia (SAA) includes immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG) and ciclosporin A. However, the optimal dose for rabbit ATG has yet to be established. We herein report the first prospective, randomized, multicentre study comparing two doses of rabbit ATG in patients with SAA. Patients with SAA who required initial IST in Japan (n = 89), China (n = 85) and Korea (n = 48) were enrolled between May 2012 and October 2017. A 1:1 block randomization was employed for two doses of rabbit ATG. In total, 222 patients were randomized, with 112 patients receiving 2·5 mg/kg and 110 receiving 3·5 mg/kg of rabbit ATG for 5 days. The primary endpoint was the haematological response at day 180. After 6 months, no significant difference in response rates was observed between the 2·5 and 3·5 mg/kg groups (49% vs. 48%, P = 0·894). Overall survival at 3 years was similar between the two groups [85% (95% confidence interval [CI], 76%−91%) vs. 91% (95% CI, 82%−96%); P = 0·107]. The current study revealed no significant differences in the efficacy and safety between the 2·5 and 3·5 mg/kg doses of rabbit ATG in patients with SAA. Trial registration: UMIN000011134.

DOI： 10.1111/bjh.16055

Risk factors for absence of catch-up growth in small for gestational age very low-birthweight infants Reviewed

Arai S., Sato Y., Muramatsu H., Yamamoto H., Aoki F., Okai Y., Kataoka S., Hanada Y., Hamada M., Morimoto Y., Kojima S., Natsume J., Takahashi Y., Sugiyama Y., Hoshino S., Kawada J., Kidokoro H., Hayakawa M., Hattori T., Kato Y., Yasuda A., Oshiro M., Takemoto K., Nishimura N., Hayashi S., Hyodo R., Ito M., Narahara S., Ieda K., Yamamoto H.

Pediatrics International Vol. 61 ( 9 ) page： 889 - 894 2019.9

Language：Japanese Publisher：Pediatrics International

Background: Many small for gestational age (SGA) infants have catch-up growth during the first 2 years of life, but approximately 10% have no catch-up growth, and short stature continues into adulthood. Identification of risk factors for absence of catch-up growth at an early age may be useful for earlier diagnosis and earlier treatment. Methods: This was a retrospective multicenter study. The subjects were SGA infants with very low-birthweight (VLBW), who were followed up until the age of 3 years. The risk factors for absence of catch-up growth were identified on statistical analysis. Results: Of the 217 SGA infants in this study, 181 were in the catch-up group and 36 were in the no catch-up group. The catch-up rate was 83%. On multivariate analysis adjusted for gestational age, birthweight, birth height, and birth head circumference, multipara, Z and ΔZ scores of length at 12 months of corrected age, and the Z score of height at 24 months of corrected age were risk factors for lack of catch-up at 3 years. Conclusions: The length Z and ΔZ scores at 12 months of corrected age may be useful for an earlier diagnosis and earlier initiation of growth hormone treatment in VLBW infants.

DOI： 10.1111/ped.13939

Whole abdominopelvic intensity-modulated radiation therapy for peritoneal disseminated rhabdomyosarcoma with three-year follow-up: A case report Reviewed Open Access

Kawamura M., Okudaira K., Itoh Y., Kamomae T., Nishikawa E., Muramatsu H., Takahashi Y., Yokota K., Naganawa S.

Radiation Oncology Vol. 14 ( 1 ) page： 127 2019.7

Language：Japanese Publisher：Radiation Oncology

Background: The role of local radiotherapy in the treatment of metastatic rhabdomyosarcoma is important. However, with peritoneal dissemination, the application of local therapy is challenging. Although there are few reports addressing the efficacy of the whole abdominopelvic irradiation to peritoneal disseminated rhabdomyosarcoma patients, no precise curse of treatment nor the follow up result is explained in paper nor in the text. Case presentation: Six years old rhabdomyosarcoma boy with peritoneal dissemination was treated at our facility under COG D9803 protocol (vincristine, dactinomycin, and cyclophosphamide (VAC)). He underwent tumor resection on the 14th week according to the protocol. During surgery, the 2-cm residual tumor was completely resected, but in the pelvis, numerous nodules that were suspected as peritoneal disseminated tumors were observed. We administered 30 Gy/20fr whole abdominopelvic radiotherapy using volumetric modulated arc therapy (VMAT) technique and a 6 Gy sequential boost to pelvis after the surgery and completed the protocol treatment. During the course of treatment, the patient experienced G4 hematological toxicity and received multiple transfusions, particularly after whole abdominopelvic irradiation. He has achieved complete remission and is alive without evidence of recurrence and severe late adverse effect for 3 years. In terms of growth, his height and weight are within the average values for Japanese boys at the same age. Conclusion: By using the VMAT technique, a patient with peritoneal disseminated rhabdomyosarcoma can be treated, and a dose of 30 Gy to the whole abdominopelvis with concurrent chemotherapy may be tolerable.

DOI： 10.1186/s13014-019-1333-x

Elucidation of the pathogenic mechanism and potential treatment strategy for a female patient with spastic paraplegia derived from a single-nucleotide deletion in PLP1 Reviewed

Yamamoto-Shimojima K., Imaizumi T., Aoki Y., Inoue K., Kaname T., Okuno Y., Muramatsu H., Kato K., Yamamoto T.

Journal of Human Genetics Vol. 64 ( 7 ) page： 665 - 671 2019.7

Language：Japanese Publisher：Journal of Human Genetics

Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive disorder caused by abnormalities in the gene PLP1. Most females harboring heterozygous PLP1 abnormalities are basically asymptomatic. However, as a result of abnormal patterns of X-chromosome inactivation, it is possible for some female carriers to be symptomatic. Whole-exome sequencing of a female patient with unknown spastic paraplegia was performed to obtain a molecular diagnosis. As a result, a de novo heterozygous single-nucleotide deletion in PLP1 [NM_000533.5(PLP1_v001):c.783del; p.Thr262Leufs*20] was identified. RNA sequencing was performed in a patient-derived lymphoblastoid cell line, confirming mono-allelic expression of the mutated allele and abnormal inactivation of the wild-type allele. The patient-derived lymphoblastoid cell line was then treated with VX680 or 5azadC, which resulted in restored expression of the wild-type allele. These two agents thus have the potential to reverse inappropriately-skewed inactivation of the X-chromosome.

DOI： 10.1038/s10038-019-0600-x

Correction: Treatment with silver nitrate versus topical steroid treatment for umbilical granuloma: A non-inferiority randomized control trial (PLoS ONE (2018) 13: 2 (e0192688) DOI: 10.1371/journal.pone.0192688) Reviewed Open Access

Ogawa C., Sato Y., Suzuki C., Mano A., Tashiro A., Niwa T., Hamazaki S., Tanahashi Y., Suzumura M., Hayano S., Hayakawa M., Tsuji T., Hoshino S., Sugiyama Y., Kidokoro H., Kawada J.i., Muramatsu H., Hirakawa A., Ando M., Natsume J., Kojima S.

PLoS ONE Vol. 14 ( 6 ) page： e0218205 2019.6

Language：Japanese Publisher：PLoS ONE

In the TSO treatment subsection of the Materials and methods section, the concentration of betamethasone valerate ointment is incorrect. The correct sentence is: Patients were applied with 0.12% betamethasone valerate ointment to the lesion twice a day after washing or bathing by parents.

DOI： 10.1371/journal.pone.0218205

Design of a prospective multicenter randomized controlled trial evaluating the effects of gastric lavage on coffee-ground emesis in neonates: study protocol Reviewed Open Access

Maeda T., Sato Y., Hirakawa A., Nakatochi M., Kinoshita F., Suzuki T., Ichimura S., Ito R., Kudo R., Suzuki M., Hoshino S., Sugiyama Y., Muramatsu H., Kidokoro H., Kawada J.I., Takahashi Y.

Nagoya journal of medical science Vol. 81 ( 2 ) page： 227 - 232 2019.5

Language：Japanese Publisher：Nagoya journal of medical science

Neonates who swallow a considerable amount of maternal blood may exhibit vomiting and suckling disorder during the first few days of the postnatal period. Some clinicians treat these neonates with gastric lavage (GL) to prevent vomiting and the establishment of enteral feeding empirically, but there was no study assessing the effect of GL for neonates with coffee-ground emesis. We designed a multicenter randomized controlled trial to evaluate the efficacy and safety of GL in neonates with coffee-ground emesis. Vigorous neonates with birth weight ranging from 2500 g to 3999 g and gestational age between 37w0d and 41w6d who presented with coffee-ground emesis on more than twice and diagnosed as false melena, were divided into two groups using computerized randomization. We defined feeding intolerance (FI) as (1) ≥2 vomiting episodes in 4h or ≥3 episodes in 24h and/or (2) feeding failure on at least two occasions because of retching or poor sucking. Primary outcome is percentage of infants who present FI within 24 hours from admission. We also assessed the residual volumes, number of vomiting episodes, percentage of weight reduction at postnatal day 4, rates of body weight gain at 1 month of age, and peak serum total bilirubin value before discharge. To our knowledge, this is the first study to evaluate the safety and efficacy of GL for neonates with coffee-ground emesis. This trial is registered at UMIN Clinical Trials Registry as UMIN000026483.

DOI： 10.18999/nagjms.81.2.227

Comparison of high-dose and low-dose corticosteroid therapy for refractory Mycoplasma pneumoniae pneumonia in children Reviewed Open Access

Okumura T., Kawada J.i., Tanaka M., Narita K., Ishiguro T., Hirayama Y., Narahara S., Tsuji G., Sugiyama Y., Suzuki M., Tsuji T., Hoshino S., Nakatochi M., Muramatsu H., Kidokoro H., Takahashi Y., Sato Y., Miyajima Y., Uno N., Nagai N., Ando S., Sudo Y., Naruse K., Takahashi Y., Suzui R., Nagata Y., Kawabe T., Shibata M., Shibata Y., Morishita M., Kajita M., Ito T., Kido S., Hasegawa S., Ikeda K., Tokumo N., Kato M., Kato K., Fukumi D., Doi S., Omori M., Watanabe N., Takada H.

Journal of Infection and Chemotherapy Vol. 25 ( 5 ) page： 346 - 350 2019.5

Language：Japanese Publisher：Journal of Infection and Chemotherapy

Background: Mycoplasma pneumoniae pneumonia (MPP) is generally a self-limiting disease, but it may become refractory. It is thought that refractory MPP is linked to the excessive immunologic responses of the host. Consequently, the use of adjunctive systemic corticosteroids may have beneficial effects. In this study, we compared the effects of high- and low-dose corticosteroid therapy in a pediatric population with refractory MPP. Methods: We retrospectively collected data from 91 pediatric MPP patients treated with adjunctive systemic corticosteroids between April 2014 and October 2016. The patients were divided into the following two groups: high-dose corticosteroid group (2 mg/kg/day or more of prednisolone equivalents; n = 38) and low-dose corticosteroid group (<2 mg/kg/day; n = 53). Additionally, we compared the number of febrile days post-corticosteroid administration. We used 25 paired patients in a propensity score matching analysis to correct for confounding factors both by age and by days (from onset till corticosteroid therapy initiation). Results: We observed that in the high-dose corticosteroid group defervescence following corticosteroid therapy initiation was achieved significantly earlier and length of hospitalization was significantly shorter (0.8 ± 1.0 vs. 1.5 ± 1.4 days and 8.2 ± 2.4 vs. 10.7 ± 2.7 days, respectively). In the propensity score matching, we observed that significant differences in the length of fever following corticosteroid therapy initiation and hospitalization were still present. Further, neither of the groups developed corticosteroid-related adverse events. Conclusion: Our results suggest that patients with refractory MPP treated with high-dose corticosteroid could achieve defervescence earlier and have a shorter hospitalization.

DOI： 10.1016/j.jiac.2019.01.003

Successful hematopoietic stem cell transplantation from an HLA-mismatched parent for engraftment failure after unrelated cord blood transplantation in patients with juvenile myelomonocytic leukemia: Report of two cases Reviewed

Akahane K., Watanabe A., Furuichi Y., Somazu S., Oshiro H., Goi K., Sakashita K., Muramatsu H., Hama A., Takahashi Y., Koike K., Kojima S., Sugita K., Inukai T.

Pediatric Transplantation Vol. 23 ( 3 ) page： e13378 2019.5

Language：Japanese Publisher：Pediatric Transplantation

JMML is an aggressive hematopoietic malignancy of early childhood, and allogeneic HSCT is the only curative treatment for this disease. Umbilical cord blood is one of donor sources for HSCT in JMML patients who do not have an HLA-compatible relative, but engraftment failure remains a major problem. Here, we report two cases of JMML who were successfully rescued by HSCT from an HLA-mismatched parent after development of primary engraftment failure following unrelated CBT. Both patients had severe splenomegaly and underwent unrelated CBT from an HLA-mismatched donor. Immediately after diagnosis of engraftment failure, both patients underwent HSCT from their parent. For the second HSCT, we used RIC regimens consisting of FLU, CY, and a low dose of rabbit ATG with or without TBI and additionally administered ETP considering their persistent severe splenomegaly. Both patients achieved engraftment without severe treatment-related adverse effects. After engraftment of second HSCT, their splenomegaly was rapidly regressed, and both patients showed no sign of relapse for over 4 years. These observations demonstrate that HSCT from an HLA-mismatched parent could be a feasible salvage treatment for primary engraftment failure in JMML patients.

DOI： 10.1111/petr.13378

KLF1 mutation E325K induces cell cycle arrest in erythroid cells differentiated from congenital dyserythropoietic anemia patient-specific induced pluripotent stem cells Reviewed

Kohara H., Utsugisawa T., Sakamoto C., Hirose L., Ogawa Y., Ogura H., Sugawara A., Liao J., Aoki T., Iwasaki T., Asai T., Doisaki S., Okuno Y., Muramatsu H., Abe T., Kurita R., Miyamoto S., Sakuma T., Shiba M., Yamamoto T., Ohga S., Yoshida K., Ogawa S., Ito E., Kojima S., Kanno H., Tani K.

Experimental Hematology Vol. 73 page： 25 - 37.e8 2019.5

Language：Japanese Publisher：Experimental Hematology

Krüppel-like factor 1 (KLF1), a transcription factor controlling definitive erythropoiesis, is involved in sequential control of terminal cell division and enucleation via fine regulation of key cell cycle regulator gene expression in erythroid lineage cells. Type IV congenital dyserythropoietic anemia (CDA)is caused by a monoallelic mutation at the second zinc finger of KLF1 (c.973G>A, p.E325K). We recently diagnosed a female patient with type IV CDA with the identical missense mutation. To understand the mechanism underlying the dyserythropoiesis caused by the mutation, we generated induced pluripotent stem cells (iPSCs)from the CDA patient (CDA-iPSCs). The erythroid cells that differentiated from CDA-iPSCs (CDA-erythroid cells)displayed multinucleated morphology, absence of CD44, and dysregulation of the KLF1 target gene expression. In addition, uptake of bromodeoxyuridine by CDA-erythroid cells was significantly decreased at the CD235a+/CD71+ stage, and microarray analysis revealed that cell cycle regulator genes were dysregulated, with increased expression of negative regulators such as CDKN2C and CDKN2A. Furthermore, inducible expression of the KLF1 E325K, but not the wild-type KLF1, caused a cell cycle arrest at the G1 phase in CDA-erythroid cells. Microarray analysis of CDA-erythroid cells and real-time polymerase chain reaction analysis of the KLF1 E325K inducible expression system also revealed altered expression of several KLF1 target genes including erythrocyte membrane protein band 4.1 (EPB41), EPB42, glutathione disulfide reductase (GSR), glucose phosphate isomerase (GPI), and ATPase phospholipid transporting 8A1 (ATP8A1). Our data indicate that the E325K mutation in KLF1 is associated with disruption of transcriptional control of cell cycle regulators in association with erythroid membrane or enzyme abnormalities, leading to dyserythropoiesis.

DOI： 10.1016/j.exphem.2019.03.001

Defective Epstein–Barr virus in chronic active infection and haematological malignancy Reviewed

Okuno Y., Murata T., Sato Y., Muramatsu H., Ito Y., Watanabe T., Okuno T., Murakami N., Yoshida K., Sawada A., Inoue M., Kawa K., Seto M., Ohshima K., Shiraishi Y., Chiba K., Tanaka H., Miyano S., Narita Y., Yoshida M., Goshima F., Kawada J.i., Nishida T., Kiyoi H., Kato S., Nakamura S., Morishima S., Yoshikawa T., Fujiwara S., Shimizu N., Isobe Y., Noguchi M., Kikuta A., Iwatsuki K., Takahashi Y., Kojima S., Ogawa S., Kimura H.

Nature Microbiology Vol. 4 ( 3 ) page： 404 - 413 2019.3

Language：Japanese Publisher：Nature Microbiology

Epstein–Barr virus (EBV) infection is highly prevalent in humans and is implicated in various diseases, including cancer1,2. Chronic active EBV infection (CAEBV) is an intractable disease classified as a lymphoproliferative disorder in the 2016 World Health Organization lymphoma classification1,2. CAEBV is characterized by EBV-infected T/natural killer (NK) cells and recurrent/persistent infectious mononucleosis-like symptoms3. Here, we show that CAEBV originates from an EBV-infected lymphoid progenitor that acquires DDX3X and other mutations, causing clonal evolution comprising multiple cell lineages. Conspicuously, the EBV genome in CAEBV patients harboured frequent intragenic deletions (27/77) that were also common in various EBV-associated neoplastic disorders (28/61), including extranodal NK/T-cell lymphoma and EBV-positive diffuse large B-cell lymphoma, but were not detected in infectious mononucleosis or post-transplant lymphoproliferative disorders (0/47), which suggests a unique role of these mutations in neoplastic proliferation of EBV-infected cells. These deletions frequently affected BamHI A rightward transcript microRNA clusters (31 cases) and several genes that are essential for producing viral particles (20 cases). The deletions observed in our study are thought to reactivate the lytic cycle by upregulating the expression of two immediate early genes, BZLF1 and BRLF14–7, while averting viral production and subsequent cell lysis. In fact, the deletion of one of the essential genes, BALF5, resulted in upregulation of the lytic cycle and the promotion of lymphomagenesis in a xenograft model. Our findings highlight a pathogenic link between intragenic EBV deletions and EBV-associated neoplastic proliferations.

DOI： 10.1038/s41564-018-0334-0

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