Faculty Profiles - MURAMATSU, Hideki

Papers - MURAMATSU, Hideki

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ACTN1 mutations cause congenital macrothrombocytopenia Reviewed

Kunishima S., Okuno Y., Yoshida K., Shiraishi Y., Sanada M., Muramatsu H., Chiba K., Tanaka H., Miyazaki K., Sakai M., Ohtake M., Kobayashi R., Iguchi A., Niimi G., Otsu M., Takahashi Y., Miyano S., Saito H., Kojima S., Ogawa S.

American Journal of Human Genetics Vol. 92 ( 3 ) page： 431 - 438 2013.3

Language：Japanese Publisher：American Journal of Human Genetics

Congenital macrothrombocytopenia (CMTP) is a heterogeneous group of rare platelet disorders characterized by a congenital reduction of platelet counts and abnormally large platelets, for which CMTP-causing mutations are only found in approximately half the cases. We herein performed whole-exome sequencing and targeted Sanger sequencing to identify mutations that cause CMTP, in which a dominant mode of transmission had been suspected but for which no known responsible mutations have been documented. In 13 Japanese CMTP-affected pedigrees, we identified six (46%) affected by ACTN1 variants cosegregating with CMTP. In the entire cohort, ACNT1 variants accounted for 5.5% of the dominant forms of CMTP cases and represented the fourth most common cause in Japanese individuals. Individuals with ACTN1 variants presented with moderate macrothrombocytopenia with anisocytosis but were either asymptomatic or had only a modest bleeding tendency. ACTN1 encodes α-actinin-1, a member of the actin-crosslinking protein superfamily that participates in the organization of the cytoskeleton. In vitro transfection experiments in Chinese hamster ovary cells demonstrated that altered α-actinin-1 disrupted the normal actin-based cytoskeletal structure. Moreover, transduction of mouse fetal liver-derived megakaryocytes with disease-associated ACTN1 variants caused a disorganized actin-based cytoskeleton in megakaryocytes, resulting in the production of abnormally large proplatelet tips, which were reduced in number. Our findings provide an insight into the pathogenesis of CMTP. © 2013 The American Society of Human Genetics.

DOI： 10.1016/j.ajhg.2013.01.015

Rabbit antithymocyte globulin and cyclosporine as first-line therapy for children with acquired aplastic anemia Reviewed

Takahashi Y., Muramatsu H., Sakata N., Hyakuna N., Hamamoto K., Kobayashi R., Ito E., Yagasaki H., Ohara A., Kikuchi A., Morimoto A., Yabe H., Kudo K., Watanabe K.I., Ohga S., Kojima S.

Blood Vol. 121 ( 5 ) page： 862 - 863 2013.1

Spliceosomal gene mutations are frequent events in the diverse mutational spectrum of chronic myelomonocytic leukemia but largely absent in juvenile myelomonocytic leukemia Reviewed

Kar S.A., Jankowska A., Makishima H., Visconte V., Jerez A., Sugimoto Y., Muramatsu H., Traina F., Afable M., Guinta K., Tiu R.V., Przychodzen B., Sakaguchi H., Kojima S., Sekeres M.A., List A.F., McDevitt M.A., Maciejewski J.P.

Haematologica Vol. 98 ( 1 ) page： 107 - 113 2013.1

Language：Japanese Publisher：Haematologica

Chronic myelomonocytic leukemia is a heterogeneous disease with multifactorial molecular pathogenesis. Various recurrent somatic mutations have been detected alone or in combination in chronic myelomonocytic leukemia. Recently, recurrent mutations in spliceosomal genes have been discovered. We investigated the contribution of U2AF1, SRSF2 and SF3B1 mutations in the pathogenesis of chronic myelomonocytic leukemia and closely related diseases. We genotyped a cohort of patients with chronic myelomonocytic leukemia, secondary acute myeloid leukemia derived from chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia for somatic mutations in U2AF1, SRSF2, SF3B1 and in the other 12 most frequently affected genes in these conditions. Chromosomal abnormalities were assessed by nucleotide polymorphism array-based karyotyping. The presence of molecular lesions was correlated with clinical endpoints. Mutations in SRSF2, U2AF1 and SF3B1 were found in 32%, 13% and 6% of cases of chronic myelomonocytic leukemia, secondary acute myeloid leukemia derived from chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia, respectively. Spliceosomal genes were affected in various combinations with other mutations, including TET2, ASXL1, CBL, EZH2, RAS, IDH1/2, DNMT3A, TP53, UTX and RUNX1. Worse overall survival was associated with mutations in U2AF1 (P=0.047) and DNMT3A (P=0.015). RAS mutations had an impact on overall survival in secondary acute myeloid leukemia (P=0.0456). By comparison, our screening of juvenile myelomonocytic leukemia cases showed mutations in ASXL1 (4%), CBL (10%), and RAS (6%) but not in IDH1/2, TET2, EZH2, DNMT3A or the three spliceosomal genes. SRSF2 and U2AF1 along with TET2 (48%) and ASXL1 (38%) are frequently affected by somatic mutations in chronic myelomonocytic leukemia, quite distinctly from the profile seen in juvenile myelomonocytic leukemia. Our data also suggest that spliceosomal mutations are of ancestral origin. © 2013 Ferrata Storti Foundation.

DOI： 10.3324/haematol.2012.064048

Progressive hearing loss following acquired cytomegalovirus infection in an immunocompromised child Reviewed

Kato K., Otake H., Tagaya M., Takahashi Y., Ito Y., Hama A., Muramatsu H., Kojima S., Naganawa S., Nakashima T.

American Journal of Otolaryngology - Head and Neck Medicine and Surgery Vol. 34 ( 1 ) page： 89 - 92 2013.1

Language：Japanese Publisher：American Journal of Otolaryngology - Head and Neck Medicine and Surgery

We report a rare case of progressive hearing loss after acquired CMV infection in a child with Langerhans cell histiocytosis (LCH). A 5-month-old female was diagnosed as having LCH. When she was 14 months old, she received an unrelated donor umbilical cord blood transfusion for the treatment of intractable LCH. CMV infection was confirmed after the blood transfusion. Because her own umbilical cord had no CMV, the CMV infection was not congenital. When she was 7 years old, mixed hearing loss was noted with bilateral otitis media with effusion. After that time, the sensorineural hearing loss progressed to bilateral profound hearing loss over 3 years. Three-dimensional fluid-attenuated inversion recovery magnetic resonance imaging with gadolinium contrast enhancement revealed a high intensity area in the inner ear that suggested bilateral labyrinthitis. This case demonstrates the possibility that, under the immunodeficiency, the acquired CMV infection causes progressive sensorineural hearing loss. © 2013 Elsevier Inc.

DOI： 10.1016/j.amjoto.2012.09.006

Mutational analysis of RNA splicing machinery components in 206 children with myeloid malignancies Reviewed

Sakaguchi H., Makishima H., Muramatsu H., Visconte V., Jerez A., Jankowska A.M., Tiu R.V., Maciejewski J.P., Kojima S.

Leukemia Research Vol. 36 ( 12 ) 2012.12

Mutations profile of polycythemia vera and essential thrombocythemia among Japanese children Reviewed

Ismael O., Shimada A., Hama A., Sakaguchi H., Doisaki S., Muramatsu H., Yoshida N., Ito M., Takahashi Y., Akita N., Sunami S., Ohtsuka Y., Asada Y., Fujisaki H., Kojima S.

Pediatric Blood and Cancer Vol. 59 ( 3 ) page： 530 - 535 2012.9

Language：Japanese Publisher：Pediatric Blood and Cancer

Background: Acquired somatic mutations of JAK2 have been reported to play a pivotal role in the pathogenesis of BCR-ABL1-negative myeloproliferative neoplasm (MPN). However, the molecular characteristics of childhood MPN remain to be elucidated. Patient and Methods: We investigated a group of pediatric patients diagnosed either with essential thrombocythemia (ET; N=9) or polycythemia vera (PV; N=4) according to WHO criteria (median age=10 years; range 1.5-15 years) in whom direct sequencing was performed for the existence of genetic alterations in JAK2, MPL, TET2, ASXL1, CBL, IDH1, and IDH2. More sensitive allele specific polymerase chain reaction was used for JAK2 V617F genotyping. Results: We found three patients harbor JAK2 V617F mutation (2/9 ET and 1/4 PV). Bone marrow examination showed small and large megakaryocytes with dysplastic features in JAK2 V617F-positive ET patients compared to those without JAK2 V617F. We identified a previously unrecognized missense mutation at codon 1230 in exon 12 of ASXL1 gene in ET and PV patients (1/9 ET and 1/4 PV). Otherwise, no genetic alterations could be detected in JAK2 exon 12, MPL, TET2, CBL, IDH1, and IDH2 in all ET and PV patients. Conclusion: Although JAK2 mutations in childhood ET and PV are not as frequent as reported in adult patients, JAK2 is the most frequently mutated gene in childhood MPN known so far. Owing to the presence of childhood MPN without any genetic alterations in JAK2, MPL, TET2, ASXL1, CBL, IDH1, and IDH2, new biological markers have to be found. © 2011 Wiley Periodicals, Inc.

DOI： 10.1002/pbc.23409

Somatic mosaicism for oncogenic NRAS mutations in juvenile myelomonocytic leukemia Reviewed

Doisaki S., Muramatsu H., Shimada A., Takahashi Y., Mori-Ezaki M., Sato M., Kawaguchi H., Kinoshita A., Sotomatsu M., Hayashi Y., Furukawa-Hibi Y., Yamada K., Hoshino H., Kiyoi H., Yoshida N., Sakaguchi H., Narita A., Wang X., Ismael O., Xu Y., Nishio N., Tanaka M., Hama A., Koike K., Kojima S.

Blood Vol. 120 ( 7 ) page： 1485 - 1488 2012.8

Language：Japanese Publisher：Blood

Juvenile myelomonocytic leukemia (JMML) is a rare pediatric myeloid neoplasm characterized by excessive proliferation of myelomonocytic cells. Somatic mutations in genes involved in GM-CSF signal transduction, such as NRAS, KRAS, PTPN11, NF1, and CBL, have been identified in more than 70% of children with JMML. In the present study, we report 2 patients with somatic mosaicism for oncogenic NRAS mutations (G12D and G12S) associated with the development of JMML. The mutated allele frequencies quantified by pyrosequencing were various and ranged from 3%-50% in BM and other somatic cells (ie, buccal smear cells, hair bulbs, or nails). Both patients experienced spontaneous improvement of clinical symptoms and leukocytosis due to JMML without hematopoietic stem cell transplantation. These patients are the first reported to have somatic mosaicism for oncogenic NRAS mutations. The clinical course of these patients suggests that NRAS mosaicism may be associated with a mild disease phenotype in JMML. © 2012 by The American Society of Hematology.

DOI： 10.1182/blood-2012-02-406090

Casitas B-cell lymphoma mutation in childhood T-cell acute lymphoblastic leukemia Reviewed

Saito Y., Aoki Y., Muramatsu H., Makishima H., Maciejewski J.P., Imaizumi M., Rikiishi T., Sasahara Y., Kure S., Niihori T., Tsuchiya S., Kojima S., Matsubara Y.

Leukemia Research Vol. 36 ( 8 ) page： 1009 - 1015 2012.8

Language：Japanese Publisher：Leukemia Research

Somatic CBL mutations have been reported in a variety of myeloid neoplasms but are rare in acute lymphoblastic leukemia (ALL). We analyzed 77 samples from hematologic malignancies, identifying a somatic mutation in CBL (p.C381R) in one patient with T-ALL that was associated with a uniparental disomy at the CBL locus and a germline heterozygous mutation in one patient with JMML. Two NOTCH1 mutations and homozygous deletions in LEF1 and CDKN2A were identified in T-ALL cells. The activation of the RAS pathway was enhanced, and activation of the NOTCH1 pathway was inhibited in NIH 3T3 cells that expressed p.C381R. This study appears to be the first to identify a CBL mutation in T-ALL. © 2012 Elsevier Ltd.

DOI： 10.1016/j.leukres.2012.04.018

Mutation in the THPO gene is not associated with aplastic anaemia in Japanese children Reviewed

Wang X., Muramatsu H., Sakaguchi H., Xu Y., Narita A., Tsumura Y., Doisaki S., Tanaka M., Ismael O., Shimada A., Hama A., Takahashi Y., Kojima S.

British Journal of Haematology Vol. 158 ( 4 ) page： 553 - 555 2012.8

CBL mutation-related patterns of phosphorylation and sensitivity to tyrosine kinase inhibitors Reviewed

Makishima H., Sugimoto Y., Szpurka H., Clemente M.J., Ng K.P., Muramatsu H., O'Keefe C., Saunthararajah Y., MacIejewski J.P.

Leukemia Vol. 26 ( 7 ) page： 1547 - 1554 2012.7

Language：Japanese Publisher：Leukemia

Recurrent homozygous CBL-inactivating mutations in myeloid malignancies decrease ubiquitin ligase activity that inactivates SRC family kinases (SFK) and receptor tyrosine kinases (RTK). However, the most important SFK and RTK affected by these mutations, and hence, the most important therapeutic targets, have not been clearly characterized. We compared SFK and RTK pathway activity and inhibitors in acute myeloid leukemia cell lines containing homozygous R420Q mutation (GDM-1), heterozygous deletion (MOLM13) and wild-type (WT) CBL (THP1, U937). As expected with CBL loss, GDM-1 displayed high KIT expression and granulocyte-macrophage colony-stimulating factor (GM-CSF) hypersensitivity. Ectopic expression of WT CBL decreased GDM-1 proliferation but not cell lines with WT CBL. GDM-1, but not the other cell lines, was highly sensitive to growth inhibition by dasatinib (dual SFK and RTK inhibitor, LD50 50 nM); there was less or no selective inhibition of GDM-1 growth by sunitinib (RTK inhibitor), imatinib (ABL, KIT inhibitor), or PP2 (SFK inhibitor). Phosphoprotein analysis identified phosphorylation targets uniquely inhibited by dasatinib treatment of GDM-1, including a number of proteins in the KIT and GM-CSF receptor pathways (for example, KIT Tyr721, STAT3 Tyr705). In conclusion, the promiscuous effects of CBL loss on SFK and RTK signaling appear to be best targeted by dual SFK and RTK inhibition. © 2012 Macmillan Publishers Limited.

DOI： 10.1038/leu.2012.7

De novo childhood myelodysplastic/myeloproliferative disease with unique molecular characteristics Reviewed

Ismael O., Shimada A., Hama A., Elshazley M., Muramatsu H., Goto A., Sakaguchi H., Tanaka M., Takahashi Y., Yinyan X., Fukuda M., Miyajima Y., Yamashita Y., Horibe K., Hanada R., Ito M., Kojima S.

British Journal of Haematology Vol. 158 ( 1 ) page： 129 - 137 2012.7

Language：Japanese Publisher：British Journal of Haematology

Myelodysplastic/myeloproliferative uclassifiable (MDS/MPN-U) is a rare myeloid neoplasm characterized by myelodysplasia and myeloproliferation at the time of initial presentation, which is usually a diagnosis of exclusion. The molecular pathogenesis of MDS/MPN-U patients remains to be elucidated. Among five patients diagnosed with MDS/MPN-U, three patients harboured RUNX1 (AML1) mutations; one carried somatic mosaicism of RUNX1 mutation with JAK2V617F mutation and one had dual RUNX1 and FLT3-internal tandem duplication mutations with progression to acute myeloid leukaemia (AML). Germline mutation of TP53 was detected as a sole genetic lesion in one patient. JAK2V617F and somatic mosaicism of KRAS and TET2 mutations co-existed in one patient. Otherwise, no alterations were detected in PTPN11, NRAS, CBL and ASXL1 genes. ETV6-PDGFRB fusion transcript was not detected in all patients. Four patients recieved haematopoietic stem cell transplantation (HSCT); three patients relapsed and one achieved complete remission after three donor lymphocyte infusions. Our findings suggest that the mutational spectrum observed in childhood MDS/MPN-U is quite different from that seen in juvenile myelomonocytic leukaemia and, to some extent, resemble chronic myelomonocytic leukaemia. Moreover, two patients had constitutional alterations of genes frequently found in AML. Further investigations are required to define the roles of these genetic alterations in the pathogenesis of childhood MDS/MPN-U. © 2012 Blackwell Publishing Ltd.

DOI： 10.1111/j.1365-2141.2012.09140.x

Loss of heterozygosity in 7q myeloid disorders: Clinical associations and genomic pathogenesis Reviewed

Jerez A., Sugimoto Y., Makishima H., Verma A., Jankowska A.M., Przychodzen B., Visconte V., Tiu R.V., O'Keefe C.L., Mohamedali A.M., Kulasekararaj A.G., Pellagatti A., McGraw K., Muramatsu H., Moliterno A.R., Sekeres M.A., McDevitt M.A., Kojima S., List A., Boultwood J., Mufti G.J., Maciejewski J.P.

Blood Vol. 119 ( 25 ) page： 6109 - 6117 2012.6

Language：Japanese Publisher：Blood

Loss of heterozygosity affecting chromosome 7q is common in acute myeloid leukemia and myelodysplastic syndromes, pointing toward the essential role of this region in disease phenotype and clonal evolution. The higher resolution offered by recently developed genomic platforms may be used to establish more precise clinical correlations and identify specific target genes. We analyzed a series of patients with myeloid disorders using recent genomic technologies (1458 by single-nucleotide polymorphism arrays [SNP-A], 226 by next-generation sequencing, and 183 by expression microarrays). Using SNP-A, we identified chromosome 7q loss of heterozygosity segments in 161 of 1458 patients (11%); 26% of chronic myelomonocytic leukemia patients harbored 7q uniparental disomy, of which 41% had a homozygous EZH2 mutation. In addition, we describe an SNP-A - isolated deletion 7 hypocellular myelodysplastic syndrome subset, with a high rate of progression. Using direct and parallel sequencing, we found no recurrent mutations in typically large deletion 7q and monosomy 7 patients. In contrast, we detected a markedly decreased expression of genes included in our SNP-A defined minimally deleted regions. Although a 2-hit model is present in most patients with 7q uniparental disomy and a myeloproliferative phenotype, haplodeficient expression of defined regions of 7q may underlie pathogenesis in patients with deletions and predominant dysplastic features. © 2012 by The American Society of Hematology.

DOI： 10.1182/blood-2011-12-397620

Excellent outcome of allogeneic bone marrow transplantation for Fanconi anemia using fludarabine-based reduced-intensity conditioning regimen Reviewed

Shimada A., Takahashi Y., Muramatsu H., Hama A., Ismael O., Narita A., Sakaguchi H., Doisaki S., Nishio N., Tanaka M., Yoshida N., Matsumoto K., Kato K., Watanabe N., Kojima S.

International Journal of Hematology Vol. 95 ( 6 ) page： 675 - 679 2012.6

Language：Japanese Publisher：International Journal of Hematology

Fanconi anemia (FA) is a disorder characterized by developmental anomalies, bone marrow failure and a predisposition to malignancy. It has recently been shown that hematopoietic stem cell transplantation using fludarabine (FLU)-based reduced-intensity conditioning is an efficient and quite safe therapeutic modality. We retrospectively analyzed the outcome of bone marrow transplantation (BMT) in eight patients with FA performed in two institutes between 2001 and 2011. There were seven females and one male with a median age at diagnosis = 4.5 years (range 2-12 years). The constitutional characteristics associated with FA, such as developmental anomalies, short stature and skin pigmentation, were absent in three of the patients. One patient showed myelodysplastic features at the time of BMT. All patients received BMT using FLU, cyclophosphamide (CY) and rabbit antithymocyte globulin (ATG) either from a related donor (n = 4) or an unrelated donor (n = 4). Acute graft-versushost disease (GVHD) of grade I developed in one patient, while chronic GVHD was not observed in any patient. All patients are alive and achieved hematopoietic recovery at a median follow-up of 72 months (range 4-117 months). BMT using FLU/low-dose CY/ATG -based regimens regardless to the donor is a beneficial therapeutic approach for FA patients. © The Japanese Society of Hematology 2012.

DOI： 10.1007/s12185-012-1079-9

Central nervous system lesions due to juvenile myelomonocytic leukemia progressed in a boy undergoing first line chemotherapy Reviewed

Fukushima H., Fukushima T., Hiraki A., Suzuki R., Mahmoud S.S.A., Yoshimi A., Nakao T., Kato K., Kobayashi C., Koike K., Fukasawa M., Morishita Y., Doisaki S., Muramatsu H., Sumazaki R.

International Journal of Hematology Vol. 95 ( 5 ) page： 581 - 584 2012.5

Language：Japanese Publisher：International Journal of Hematology

Juvenile myelomonocytic leukemia is a rare malignancy that occurs in pediatric patients. Previous reports, have described leukemic cells may infiltrate many organs, such as the lungs, skin, liver, spleen, and intestines, but not the central nervous system, although central nervous system infiltration remains a point of concern in every patient with acute leukemia. Here, we present one case of a boy with juvenile myelomonocytic leukemia who developed multiple lesions in the brain while undergoing chemotherapy with 6-mercaptopurine and cytarabine. We diagnosed the central nervous system involvement by magnetic resonance imaging, cerebrospinal fluid cytology, and the patient's clinical course. He was treated with a high dose of cytarabine and intrathecal chemotherapy, then with unrelated cord blood stem cell transplantation. He has been in a first complete remission for more than 18 months after cord blood stem cell transplantation without any neurological sequelae. In conclusion, we encountered a boy with juvenile myelomonocytic leukemia who developed central nervous system lesions under standard chemotherapy. We subsequently switched treatment to central nervous system-oriented chemotherapy, which resulted in a good clinical condition and successful cord blood stem cell transplantation. © The Japanese Society of Hematology 2012.

DOI： 10.1007/s12185-012-1046-5

Incidence, clinical features, and risk factors of idiopathic pneumonia syndrome following hematopoietic stem cell transplantation in children Reviewed

Sakaguchi H., Takahashi Y., Watanabe N., Doisaki S., Muramatsu H., Hama A., Shimada A., Yagasaki H., Kudo K., Kojima S.

Pediatric Blood and Cancer Vol. 58 ( 5 ) page： 780 - 784 2012.5

Language：Japanese Publisher：Pediatric Blood and Cancer

Background: Idiopathic pneumonia syndrome (IPS) is a severe complication that can occur after hematopoietic stem cell transplantation (HSCT) and is often associated with a fatal outcome despite intensive supportive care. Procedure: To assess the incidence and risk factors of IPS, we reviewed 251 consecutive patients (median age, 7.0 years) who received HSCT at the Department of Pediatrics, Nagoya University Hospital, between January 1990 and July 2009. Results: Twenty of 251 (cumulative incidence of IPS at 2 years after HSCT, 8.0%; 95% confidence interval (CI), 5.1-12.4%) patients developed IPS. The median duration from HSCT to diagnosis of IPS was 67 days (range, 12-486 days). Patients with IPS had significantly higher 5-year transplant-related mortality compared to patients without IPS (52% (95% CI, 19-77%) vs. 13% (95% CI, 5-25%), P<0.001), and the probability of 5-year overall survival was significantly worse for patients with IPS (42% (95% CI, 25-64%) vs. 68% (95% CI, 59-76%), P=0.01). By multivariate analysis, high risk in underlying disease (HR, 2.5; 95% CI, 1.0-6.7; P=0.05) and a busulfan-containing regimen (HR, 3.5; 95% CI, 1.3-9.9; P<0.01) were identified as the independent risk factors for developing IPS. Conclusion: The prophylactic strategies for IPS in patients with these risk factors were warranted. © 2011 Wiley Periodicals, Inc.

DOI： 10.1002/pbc.23298

Autoimmune-like hepatitis following unrelated BMT successfully treated with rituximab Reviewed

Narita A., Muramatsu H., Takahashi Y., Sakaguchi H., Doisaki S., Nishio N., Hama A., Shimada A., Ito M., Kojima S.

Bone Marrow Transplantation Vol. 47 ( 4 ) page： 600 - 602 2012.4

Chronic myelomonocytic leukemia and atypical chronic myeloid leukemia: Novel pathogenetic lesions Reviewed

Muramatsu H., Makishima H., MacIejewski J.P.

Seminars in Oncology Vol. 39 ( 1 ) page： 67 - 73 2012.2

Language：Japanese Publisher：Seminars in Oncology

Chronic myelomonocytic leukemia (CMML) and atypical chronic myeloid leukemia (aCML) are distinct, yet related, entities of myelodysplastic/ myeloproliferative neoplasms (MDS/MPN) characterized by morphologic dysplasia with accumulation of monocytes or neutrophils, respectively. Our understanding of the molecular pathogenesis of CMML and aCML has advanced, mainly due to the application of novel technologies such as array-based karyotyping and next-generation sequencing. In addition to previously known recurrent aberrations, somatic uniparental disomy affecting chromosomes 3, 4, 7, and 11 frequently occurs in CMML. Novel somatic mutations of genes, including those associated with proliferation signaling (CBL, RAS, RUNX1, JAK2 (V617F)) and with modification of epigenetic status (TET2, ASXL1, UTX, EZH2) have been found. Various combinations of mutations suggest a multistep pathogenesis and may account for clinical heterogeneity. Most recently, several spliceosome- associated-gene mutations were reported and SRSF2 mutations are frequently detected in CMML. The prognostic and diagnostic significance of these molecular lesions, in particular their value as biomarkers of response or resistance to specific therapies, while uncertain now is likely to be clarified as large systematic studies come to completion. © 2012 Elsevier Inc. All rights reserved.

DOI： 10.1053/j.seminoncol.2011.11.004

Molecular lesions in childhood and adult acute megakaryoblastic leukaemia Reviewed

Hama A., Muramatsu H., Makishima H., Sugimoto Y., Szpurka H., Jasek M., O'Keefe C., Takahashi Y., Sakaguchi H., Doisaki S., Shimada A., Watanabe N., Kato K., Kiyoi H., Naoe T., Kojima S., Maciejewski J.P.

British Journal of Haematology Vol. 156 ( 3 ) page： 316 - 325 2012.2

Language：Japanese Publisher：British Journal of Haematology

While acute megakaryoblastic leukaemia (AMKL) occurs in children with (DS-AMKL) and without (paediatric non-DS-AMKL) Down syndrome, it can also affect adults without DS (adult non-DS-AMKL). We have analysed these subgroups of patients (11 children with DS-AMKL, 12 children and four adults with non-DS-AMKL) for the presence of molecular lesions, including mutations and chromosomal abnormalities studied by sequencing and single nucleotide polymorphism array-based karyotyping, respectively. In children, AMKL was associated with trisomy 21 (somatic in non-DS-AMKL), while numerical aberrations of chromosome 21 were only rarely associated with adult AMKL. DS-AMKL was also associated with recurrent somatic gains of 1q (4/11 DS-AMKL patients). In contrast to trisomy 21 and gains of 1q, other additional chromosomal lesions were evenly distributed between children and adults with AMKL. A mutational screen found GATA1 mutations in 11/12 DS-AMKL, but mutations were rare in paediatric non-DS-AMKL (1/12) and adult AMKL (0/4). JAK3 (1/11), JAK2 (1/11), and TP53 mutations (1/11) were found only in patients with DS-AMKL. ASXL1, IDH1/2, DNMT3A, RUNX1 and CBL mutations were not found in any of the patient group studied, while NRAS mutation was identified in two patients with paediatric non-DS-AMKL. © 2011 Blackwell Publishing Ltd.

DOI： 10.1111/j.1365-2141.2011.08948.x

Distinct impact of imatinib on growth at prepubertal and pubertal ages of children with chronic myeloid leukemia Reviewed

Shima H., Tokuyama M., Tanizawa A., Tono C., Hamamoto K., Muramatsu H., Watanabe A., Hotta N., Ito M., Kurosawa H., Kato K., Tsurusawa M., Horibe K., Shimada H.

Journal of Pediatrics Vol. 159 ( 4 ) page： 676 - 681 2011.10

Language：Japanese Publisher：Journal of Pediatrics

Objective: To determine the extent of growth impairment resulting from imatinib treatment in children with chronic myeloid leukemia (CML). Study design: Clinical records of 48 chronic-phase CML children administered imatinib as the first-line therapy between 2001 and 2006 were analyzed retrospectively. Cumulative change in height was assessed using the height height-SDS and converted height data from age- and sex-adjusted Japanese norms. Results: A decrease in height-SDS was observed in 72.9% of children, with a median maximum reduction in height-SDS of 0.61 during imatinib treatment. Median follow-up time was 34 months (range, 10-88 months). Growth impairment was seen predominantly in children who started imatinib at a prepubertal age compared with those who started at pubertal age. Growth velocity tended to recuperate in prepubertal children with growth impairment, as they reached pubertal age, suggesting that imatinib had little impact on growth during puberty. Conclusions: Growth impairment was a major adverse effect of long-term imatinib treatment in children with CML. We report the distinct inhibitory effect of imatinib on growth in prepubertal and pubertal children with CML. We should be aware of growth deceleration in children, especially in young children given imatinib before puberty and subjected to prolonged exposure. © 2011 Mosby Inc. All rights reserved.

DOI： 10.1016/j.jpeds.2011.03.046

Aberrant phosphorylation of STAT5 by granulocyte-macrophage colony-stimulating factor in infant cytomegalovirus infection mimicking juvenile myelomonocytic leukemia Reviewed

Nishio N., Takahashi Y., Tanaka M., Xu Y., Yoshida N., Sakaguchi H., Doisaki S., Hama A., Muramatsu H., Shimada A., Kojima S.

Leukemia Research Vol. 35 ( 9 ) page： 1261 - 1264 2011.9

Language：Japanese Publisher：Leukemia Research

Juvenile myelomonocytic leukemia (JMML) progenitor cells exhibit in vitro hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF). Phospho-specific flow cytometry using anti-phosphorylated STAT5 antibody is a new method recently reported to detect GM-CSF hypersensitivity of cells. However, colony assays using methylcellulose medium to measure GM-CSF-hypersensitivity remain as the current gold standard. Interestingly, cytomegalovirus (CMV) infection in infancy often presents with a variety of clinical symptoms that mimic JMML, with CMV giving a positive result by colony assay. We wanted to determine whether aberrant STAT5 activation occurs in CMV infection by using phospho-specific flow cytometry, and to ascertain whether this method is effective at discriminating CMV infection from JMML. Peripheral blood mononuclear cells from patients with JMML and CMV infection displayed an elevated proportion of p-STAT5 cells after low-dose GM-CSF stimulation when compared with cells from normal individuals. However, we found no significant differences in the percentage of p-STAT5 positive cells from patients with CMV infection and JMML at any doses of the GM-CSF doses used. We conclude that patients with CMV infection cannot be discriminated from patients with JMML by this new diagnostic method. © 2011 Elsevier Ltd.

DOI： 10.1016/j.leukres.2011.04.014

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