Papers - MORITAKE Hiroshi
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自家末梢血幹細胞移植後の血栓性微小血管障害にエクリズマブが著効した神経芽腫症例 Reviewed
山田 愛, 盛武 浩, 木下 真理子, 澤 大介, 今村 秀明, 上村 幸代, 此元 隆雄, 布井 博幸
日本小児科学会雑誌 121 ( 10 ) 1712 - 1718 2017.10
Language：Japanese Publishing type：Research paper (scientific journal)
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Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia Reviewed
Seki M., Kimura S., Isobe T., Yoshida K., Ueno H., Nakajima-Takagi Y., Wang C., Lin L., Kon A., Suzuki H., Shiozawa Y., Kataoka K., Fujii Y., Shiraishi Y., Chiba K., Tanaka H., Shimamura T., Masuda K., Kawamoto H., Ohki K., Kato M., Arakawa Y., Koh K., Hanada R., Moritake H., Akiyama M., Kobayashi R., Deguchi T., Hashii Y., Imamura T., Sato A., Kiyokawa N., Oka A., Hayashi Y., Takagi M., Manabe A., Ohara A., Horibe K., Sanada M., Iwama A., Mano H., Miyano S., Ogawa S., Takita J.
Nature Genetics 49 1274 - 1281 2017.8
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Nature Genetics
© 2017 Nature America, Inc., part of Springer Nature. All rights reserved. The outcome of treatment-refractory and/or relapsed pediatric T cell acute lymphoblastic leukemia (T-ALL) is extremely poor, and the genetic basis for this is not well understood. Here we report comprehensive profiling of 121 cases of pediatric T-ALL using transcriptome and/or targeted capture sequencing, through which we identified new recurrent gene fusions involving SPI1 (STMN1-SPI1 and TCF7-SPI1). Cases positive for fusions involving SPI1 (encoding PU.1), accounting for 3.9% (7/181) of the examined pediatric T-ALL cases, showed a double-negative (DN; CD4 - CD8 -) or CD8 + single-positive (SP) phenotype and had uniformly poor overall survival. These cases represent a subset of pediatric T-ALL distinguishable from the known T-ALL subsets in terms of expression of genes involved in T cell precommitment, establishment of T cell identity, and post-β-selection maturation and with respect to mutational profile. PU.1 fusion proteins retained transcriptional activity and, when constitutively expressed in mouse stem/progenitor cells, induced cell proliferation and resulted in a maturation block. Our findings highlight a unique role of SPI1 fusions in high-risk pediatric T-ALL.
DOI： 10.1038/ng.3900
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Yamato G., Shiba N., Yoshida K., Shiraishi Y., Hara Y., Ohki K., Okubo J., Okuno H., Chiba K., Tanaka H., Kinoshita A., Moritake H., Kiyokawa N., Tomizawa D., Park M., Sotomatsu M., Taga T., Adachi S., Tawa A., Horibe K., Arakawa H., Miyano S., Ogawa S., Hayashi Y.
Genes Chromosomes and Cancer 56 ( 5 ) 382 - 393 2017.5
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Genes Chromosomes and Cancer
© 2017 Wiley Periodicals, Inc. ASXL2 is an epigenetic regulator involved in polycomb repressive complex regulation or recruitment. Clinical features of pediatric acute myeloid leukemia (AML) patients with ASXL2 mutations remain unclear. Thus, we investigated frequencies of ASXL1 and ASXL2 mutations, clinical features of patients with these mutations, correlations of these mutations with other genetic alterations including BCOR/BCORL1 and cohesin complex component genes, and prognostic impact of these mutations in 369 pediatric patients with de novo AML (0–17 years). We identified 9 (2.4%) ASXL1 and 17 (4.6%) ASXL2 mutations in 25 patients. These mutations were more common in patients with t(8;21)(q22;q22)/RUNX1-RUNX1T1 (ASXL1, 6/9, 67%, P = 0.02; ASXL2, 10/17, 59%, P = 0.01). Among these 25 patients, 4 (27%) of 15 patients with t(8;21) and 6 (60%) of 10 patients without t(8;21) relapsed. However, most patients with relapse were rescued using stem cell transplantation irrespective of t(8;21). The overall survival (OS) and event-free survival (EFS) rates showed no differences among pediatric AML patients with t(8;21) and ASXL1 or ASXL2 mutations and ASXL wild-type (5-year OS, 75% vs. 100% vs. 91% and 5-year EFS, 67% vs. 80% vs. 67%). In 106 patients with t(8;21) AML, the coexistence of mutations in tyrosine kinase pathways and chromatin modifiers and/or cohesin complex component genes had no effect on prognosis. These results suggest that ASXL1 and ASXL2 mutations play key roles as cooperating mutations that induce leukemogenesis, particularly in pediatric AML patients with t(8;21), and these mutations might be associated with a better prognosis than that reported previously.
DOI： 10.1002/gcc.22443
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Ikeda T., Nakahara A., Nagano R., Utoyama M., Obara M., Moritake H., Uechi T., Mitsui J., Ishiura H., Yoshimura J., Doi K., Kenmochi N., Morishita S., Nishino I., Tsuji S., Nunoi H.
Journal of Human Genetics 62 473 - 480 2017.4
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Journal of Human Genetics
© 2017 The Japan Society of Human Genetics. Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder caused by survival motor neuron gene mutations. Variant forms of SMA accompanied by additional clinical presentations have been classified as atypical SMA and are thought to be caused by variants in as yet unidentified causative genes. Here, we presented the clinical findings of two siblings with an SMA variant followed by progressive cerebral atrophy, and the results of whole-exome sequencing analyses of the family quartet that was performed to identify potential causative variants. We identified two candidate homozygous missense variants, R942Q in the tubulin-folding cofactor D (TBCD) gene and H250Q in the bromo-adjacent homology domain and coiled-coil containing 1 (BAHCC1) gene, located on chromosome 17q25.3 with an interval of 1.4 Mbp. The in silico analysis of both variants suggested that TBCD rather than BAHCC1 was likely the pathogenic gene (TBCD sensitivity, 0.68; specificity, 0.97; BAHCC1 sensitivity, 1.00; specificity, 0.00). Thus, our results show that TBCD is a likely novel candidate gene for atypical SMA with progressive cerebral atrophy. TBCD is predicted to have important functions on tubulin integrity in motor neurons as well as in the central nervous system.
DOI： 10.1038/jhg.2016.149
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Moritake H., Obara M., Saito Y., Kashimada A., Takagi M., Funakoshi-Tago M., Fukuyama T., Yoshioka M., Inoue A., Komatsu H., Nishitoh H., Kataoka H., Nunoi H.
Human Cell 30 88 - 97 2017.4
Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：Human Cell
© 2016, Japan Human Cell Society and Springer Japan. Major facilitator superfamily domain containing 2a (Mfsd2a) is a member of the major facilitator superfamily. Mfsd2a functions as a transporter for docosahexaenoic acid and also plays a role in the unfolded protein response (UPR) upon tunicamycin (TM) exposure. UPR is involved in the pathogenesis of various human diseases. TM and thapsigargin are representative experimental reagents that induce UPR. To elucidate the detailed function of Mfsd2a in UPR in vivo, we generated Mfsd2a-deficient mice and investigated the role of Mfsd2a during UPR induced by TM or thapsigargin. Phenotypically, Mfsd2a-deficient mice were small and short-lived. No gross anatomical abnormalities in Mfsd2a-deficient mice compared with the wild-type mice were exhibited. Embryonic fibroblasts derived from Mfsd2a-null mice failed to show induction of GRP78 and DDIT3 expressions upon TM exposure but not upon Tg exposure. This phenomenon could not be overcome despite the exposure under high TM concentration. Reconstitution of Mfsd2a in Mfsd2a-null MEF showed hypersensitivity to TM. Furthermore, we examined the physiological role of Mfsd2a against TM using an in vivo mouse model. DDIT3 induction by TM was drastically attenuated in both the liver and brain of Mfsd2a-deficient mice. These results reveal that Mfsd2a plays a critical role in UPR upon TM exposure.
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Kurogi Jun, Moritake Hiroshi, Yamada Ai, Kinoshita Mariko, Sawa Daisuke, Kamimura Sachiyo, Nakamura Yoshihiro, Chosa Etsuo, Nakata Hiroshi, Moriguchi Sayaka, Asada Yujiro, Nunoi Hiroyuki
The Japanese Journal of Pediatric Hematology / Oncology 54 ( 1 ) 54 - 57 2017
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：The Japanese Society of Pediatric Hematology / Oncology
Osteosarcoma (OS) is the most common malignant bone tumor in children. Patients without metastasis are curable, whereas those with metastasis have a dismal prognosis. A recent clinical test has shown that bisphosphonate inhibits metastasis and improves the survival of osteosarcoma patients. We encountered the case of a 14-year-old male who suffered from OS of the left femur with multiple pulmonary nodules and treated with zoledronic acid (ZA) in addition to conventional chemotherapy. Histopathological examinations of the resected tumor revealed complete necrosis, suggesting a good response to preoperative chemotherapy. After the completion of chemotherapy, a few nodules disappeared, although most of the remaining pulmonary nodules showed no change in shape. Only hematological toxicity was observed during chemotherapy with ZA. The addition of ZA to conventional chemotherapy was safe in our patient. Evaluation of ZA efficacy was difficult, because the possibility that the pulmonary nodules were physiological intrapulmonary lymph nodes was high. Further experiences of treating Japanese patients will clarify the safety and efficacy of bisphosphonate for OS.
DOI： 10.11412/jspho.54.54
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Moritake H., Tanaka S., Nakayama H., Miyamura T., Iwamoto S., Shimada A., Terui K., Saito A., Shiba N., Hayashi Y., Tomizawa D., Taga T., Goto H., Hasegawa D., Horibe K., Mizutani S., Adachi S.
Pediatric Blood and Cancer 64 ( 10 ) 2017
Language：English Publishing type：Research paper (scientific journal)
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小児急性リンパ性白血病の very late relapse 例の予後 ―九州・山口小児がん治療研究グループ(KYCCSG)ALL 96/02 研究― Reviewed
野口磨依子,稲垣二郎,,岡本康裕,古賀友紀,大園秀一,新小田雄一,中山秀樹, 盛武 浩,堀田紀子,糸長伸能,野村優子,下之段秀美,市村卓也,日高靖文,河野嘉文
日本小児血液・がん学会雑誌 54 ( 5 ) 1046 - 1052 2017
Language：Japanese Publishing type：Research paper (scientific journal)
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Clinical and histological findings of autosomal dominant renal-limited disease with LMX1B mutation Reviewed
Konomoto T., Imamura H., Orita M., Tanaka E., Moritake H., Sato Y., Fujimoto S., Harita Y., Hisano S., Yoshiura K., Nunoi H.
Nephrology 21 ( 9 ) 765 - 773 2016.9
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Nephrology
© 2015 Asian Pacific Society of Nephrology Aim: Mutations of LMX1B cause nail-patella syndrome, a rare autosomal dominant disorder. Recently, LMX1B R246Q heterozygous mutations were recognised in nephropathy without extrarenal manifestation. The aim of this study was to clarify characteristics of nephropathy caused by R246Q mutation. Methods: Whole exome sequencing was performed on a large family with nonsyndromic autosomal dominant nephropathy without extrarenal manifestation. Clinical and histological findings of patients with LMX1B mutation were investigated. Results: LMX1B R246Q heterozygous mutation was identified in five patients over three generations. Proteinuria or haematoproteinuria was recognized by urinary screening from all patients in childhood. Proteinuria gradually increased to nephrotic levels and renal function decreased in adolescence. Two patients progressed to end-stage renal disease in adulthood. Renal histology demonstrated minimal change in childhood and focal segmental glomerulosclerosis in adulthood. Using electron microscopy, focal collagen deposition could be detected in glomeruli even when a “moth-eaten appearance” was not apparent in the glomerular basement membrane. In addition, podocin expression in glomerular podocytes was significantly decreased, even in the early stages of disease progression. Conclusion: Comprehensive genetic analyses and collagen or tannic acid staining may be useful for diagnosis of LMX1B-associated nephropathy. While renal prognosis of R246Q may be worse than that of typical NPS nephropathy, signs of podocytopathy can be detected during the infantile period; thus, childhood urinary screening may facilitate early detection.
DOI： 10.1111/nep.12666
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Noguchi M., Moritake H., Kamimura S., Sonoda M., Ishimura M., Inagaki J.
Bone Marrow Transplantation 53 ( 9 ) 1214 - 1217 2016.9
Language：English Publishing type：Research paper (scientific journal)
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Yamada A., Moritake H., Kinoshita M., Sawa D., Kamimura S., Iwamoto S., Yamashita Y., Inagaki J., Takahashi T., Shimada A., Obara M., Nunoi H.
Pediatrics International 58 ( 9 ) 905 - 908 2016.9
Language：English Publishing type：Research paper (scientific journal)
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Relapsed childhood acute myeloid leukemia patient with inversion of chromosome 16 harboring a low FLT3 internal tandem duplication allelic burden and KIT mutations Reviewed
Yamada A, Moritake H, Kinoshita M, Sawa, D, Kamimura S, Iwamoto S, Yamashita Y, Inagaki J, Takahashi T, Shimada A, Obara, M, Nunoi H
Pediatr Int 58 ( 9 ) 905 - 908 2016.9
Publishing type：Research paper (scientific journal)
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High event-free survival rate with minimum-dose-anthracycline treatment in childhood acute promyelocytic leukaemia: a nationwide prospective study by the Japanese Paediatric Leukaemia/Lymphoma Study Group Reviewed
Takahashi H.*, Watanabe T., Kinoshita A., Yuza Y., Moritake H., Terui K., Iwamoto S., Nakayama H., Shimada A., Kudo K., Taki T., Yabe M., Matsushita H., Yamashita Y., Koike K., Ogawa A., Kosaka Y., Tomizawa D., Taga T., Saito AM., Horibe K., Nakahata T., Miyachi H., Tawa A., Adachi S.
Br. J. Haematol. 2016.4
Language：English Publishing type：Research paper (scientific journal)
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Autoimmunity including intestinal Behçet's disease bearing the KRAS mutation in lymphocytes Reviewed
Moritake H, Takagi M, Kinoshita M, Ohara O, Yamamoto S, Moriguchi S, Nunoi H
Pediatrics 137 ( 3 ) e20152891 2016.3
Authorship：Lead author Publishing type：Research paper (scientific journal)
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Autoimmunity Including Intestinal Behcet Disease Bearing the KRAS Mutation in Lymphocytes: A Case Report. Reviewed
Moritake H, Takagi M, Kinoshita M, Ohara O, Yamamoto S, Moriguchi S, Nunoi H.
Pediatrics 2016.3
Language：English Publishing type：Research paper (scientific journal)
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Taga T., Watanabe T., Tomizawa D., Kudo K., Terui K., Moritake H., Kinoshita A., Iwamoto S., Nakayama H., Takahashi H., Shimada A., Taki T., Toki T., Ito E., Goto H., Koh K., Saito A., Horibe K., Nakahata T., Tawa A., Adachi S.
Pediatric Blood and Cancer 63 ( 2 ) 248 - 254 2016.2
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Pediatric Blood and Cancer
© 2015 Wiley Periodicals, Inc. Background: On the basis of results of previous Japanese trials for myeloid leukemia in Down syndrome (ML-DS), the efficacy of risk-oriented therapy was evaluated in the Japanese Pediatric Leukemia/Lymphoma Study Group AML-D05 study. Procedure: All patients received induction chemotherapy that consisted of pirarubicin, intermediate-dose cytarabine, and etoposide. Patients who achieved complete remission (CR) after initial induction therapy were stratified to the standard risk (SR) group and received four courses of reduced-dose intensification therapy. Patients who did not achieve CR were stratified to the high risk (HR) group and received intensified therapy that consisted of continuous or high-dose cytarabine. Results: A total of 72 patients were eligible and evaluated. One patient died of sepsis during initial induction therapy. Sixty-nine patients were stratified to SR and two patients to HR. No therapy-related deaths were observed during intensification therapy. The 3-year event-free and overall survival rates were 83.3% ± 4.4% and 87.5% ± 3.9 %, respectively. Age at diagnosis less than 2 years was a significant favorable prognostic factor for risk of relapse (P = 0.009). Conclusions: The attempt of risk-oriented prospective study for ML-DS was unsuccessful, but despite the dose reduction of chemotherapeutic agents, the overall outcome was good, and further dose reduction might be possible for specific subgroups.
DOI： 10.1002/pbc.25789
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Okamoto Y., Koga Y., Inagaki J., Ozono S., Ueda K., Shimoura M., Itonaga N., Shinkoda Y., Moritake H., Nomura Y., Nakayama H., Hotta N., Hidaka Y., Shimonodan H., Suga N., Tanabe T., Nakashima K., Fukano R., Kawano Y.
International Journal of Hematology 103 ( 2 ) 202 - 209 2016.2
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：International Journal of Hematology
© 2015, The Japanese Society of Hematology. In a previous study of childhood acute lymphoblastic leukemia (ALL) by the Kyushu–Yamaguchi Children’s Cancer Study Group, ALL-96, we achieved a 72.1 % 5-year event-free survival (EFS) and an 84.8 % 5-year overall survival (OS). In a subsequent study, ALL-02, we adopted a vincristine dexamethasone (VCR/DEX) pulse regimen as maintenance therapy in the context of the ALL-96 study using the same risk classification and treatment schedule. A total of 156 pediatric cases of ALL were treated with ALL-02. All of the patients were classified as standard-risk or high-risk. Risk stratification was based on white cell counts, immunophenotype, the presence of central nervous system (CNS) disease at diagnosis, organomegaly, and early treatment response (day 14 bone marrow status). The 7-year EFS and OS rates were 77.7 % (95 % CI 70.6–84.8 %) and 89.5 % (95 % CI 84.6–94.4 %), respectively. CNS 3 status [hazard ratio ( HR) = 5.0, p = 0.009] and high white blood cell count at diagnosis (HR = 2.6, p = 0.047) were risk factors for poor EFS in multivariate analysis. Our strategies to categorize patients into two risk groups, and to treat with a VCR/DEX pulse were feasible and reasonably effective treatments for pediatric ALL.
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Sporadic paraganglioma caused by de novo SDHB mutations in a 6-year-old girl Reviewed
Imamura H., Muroya K., Tanaka E., Konomoto T., Moritake H., Sato T., Kimura N., Takekoshi K., Nunoi H.
European Journal of Pediatrics 175 ( 1 ) 137 - 141 2016.1
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：European Journal of Pediatrics
© 2015, Springer-Verlag Berlin Heidelberg. Germline mutations in the succinate dehydrogenase complex subunit B (SDHB) gene (SDHB) cause susceptibility to paragangliomas and pheochromocytomas; however, it is exceedingly rare in childhood and especially in sporadic cases. We report the first Japanese pediatric case of paraganglioma with a de novo mutation in the SDHB gene. A 6-year-old girl with convulsions and hypertension was found to have a paravertebral abdominal tumor. Urinary and blood examinations revealed markedly elevated levels of norepinephrine. Following treatment for hypertension, the tumor was removed completely and histological findings were consistent with paraganglioma. Immunohistochemistry studies demonstrated the absence of SDHB protein expression, indicating an underlying SDH mutation with high probability. Germline mutation analysis of the SDHB gene revealed a heterozygous splice site mutation in intron 4 (C.423 + 1G > A). Subsequently, a second somatic genetic change was confirmed by multiplex ligation-dependent probe amplification (MLPA) analysis, showing that deletion of the wild-type allele resulted in loss of function of SDHB. No germline mutations in SDHB were detected in her parents. Conclusion: Genetic testing should be considered for pediatric patients with paragangliomas, even in the absence of familial history, as closer lifelong screening to detect the development of malignancy will be required for patients with SDHB mutations.What is Known• Most sporadic cases of paraganglioma with SDHB mutations occur between adolescence and adulthood.• Screening methods for carriers of SDHB mutations assessing recurrence and detecting developing metastases are yet to be standardized.What is New• The current case of an extra-adrenal paraganglioma with a de novo SDHB mutation had an onset at 6 years.• We suggest much closer periodical observation for these high-risk children.
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Boron neutron capture therapy (BNCT) as a new approach for clear cell sarcoma (CCS) treatment: Trial using a lung metastasis model of CCS. Reviewed
Andoh T, Fujimoto T, Suzuki M, Sudo T, Sakurai Y, Tanaka H, Fujita I, Fukase N,?Moritake H, Sugimoto T, Sakuma T, Sasai H, Kawamoto T, Kirihata M, Fukumori Y, Akisue T, Ono K, Ichikawa H.
Appl Radiat Isot 2015.12
Language：English Publishing type：Research paper (scientific journal)
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Paroxysmal nocturnal hemoglobinuria and telomere length predicts response to immunosuppressive therapy in pediatric aplastic anemia. Reviewed
Narita A, Muramatsu H, Sekiya Y, Okuno Y, Sakaguchi H, Nishio N, Yoshida N, Wang X, Xu Y, Kawashima N, Doisaki S, Hama A, Takahashi Y, Kudo K,?Moritake H, Kobayashi M, Kobayashi R, Ito E, Yabe H, Ohga S, Ohara A, Kojima S
Haematologica 2015.12
Language：English Publishing type：Research paper (scientific journal)