Details of a Researcher - Kataoka, Keisuke

Papers - Kataoka, Keisuke

Division display 21 - 40 of about 75 ／ All the affair displays >>

PD-1 Inhibitor Therapy in Adult T-Cell Leukemia-Lymphoma

Kataoka, K. and Ogawa, S.

N Engl J Med 379 ( 7 ) 696 2018.08

ISSN 1533-4406

Access to Document (DOI)

RNA fusions involving CD28 are rare in peripheral T-cell lymphomas and concentrate mainly in those derived from follicular helper T cells

Vallois, D., Dupuy, A., Lemonnier, F., Allen, G., Missiaglia, E., Fataccioli, V., Ortonne, N., Clavert, A., Delarue, R., Rousselet, M. C., Fabiani, B., Llamas-Gutierrez, F., Ogawa, S., Thome, M., Ko, Y. H., Kataoka, K., Gaulard, P. and de Leval, L.

Haematologica 103 ( 8 ) e360 - e363 2018.08

ISSN 1592-8721

Access to Document (DOI)

A comprehensive characterization of cis-acting splicing-associated variants in human cancer

Shiraishi, Y., Kataoka, K., Chiba, K., Okada, A., Kogure, Y., Tanaka, H., Ogawa, S. and Miyano, S.

Genome Res 28 ( 8 ) 1111 - 1125 2018.08

ISSN 1549-5469

Although many driver mutations are thought to promote carcinogenesis via abnormal splicing, the landscape of splicing-associated variants (SAVs) remains unknown due to the complexity of splicing abnormalities. Here, we developed a statistical framework to systematically identify SAVs disrupting or newly creating splice site motifs and applied it to matched whole-exome and transcriptome sequencing data from 8976 samples across 31 cancer types, generating a catalog of 14,438 SAVs. Such a large collection of SAVs enabled us to characterize their genomic features, underlying mutational processes, and influence on cancer driver genes. In fact, approximately 50% of SAVs identified were those disrupting noncanonical splice sites (non-GT-AG dinucleotides), including the third and fifth intronic bases of donor sites, or newly creating splice sites. Mutation signature analysis revealed that tobacco smoking is more strongly associated with SAVs, whereas ultraviolet exposure has less impact. SAVs showed remarkable enrichment of cancer-related genes, and as many as 14.7% of samples harbored at least one SAVs affecting them, particularly in tumor suppressors. In addition to intron retention, whose association with tumor suppressor inactivation has been previously reported, exon skipping and alternative splice site usage caused by SAVs frequently affected tumor suppressors. Finally, we described high-resolution distributions of SAVs along the gene and their splicing outcomes in commonly disrupted genes, including TP53, PIK3R1, GATA3, and CDKN2A, which offers genetic clues for understanding their functional properties. Collectively, our findings delineate a comprehensive portrait of SAVs, novel insights into transcriptional de-regulation in cancer.

Access to Document (DOI)

ADAM8 Is an Antigen of Tyrosine Kinase Inhibitor-Resistant Chronic Myeloid Leukemia Cells Identified by Patient-Derived Induced Pluripotent Stem Cells

Miyauchi, M., Koya, J., Arai, S., Yamazaki, S., Honda, A., Kataoka, K., Yoshimi, A., Taoka, K., Kumano, K. and Kurokawa, M.

Stem Cell Reports 10 ( 3 ) 1115 - 1130 2018.03

ISSN 2213-6711

Properties of cancer stem cells involved in drug resistance and relapse have significant effects on clinical outcome. Although tyrosine kinase inhibitors (TKIs) have dramatically improved survival of patients with chronic myeloid leukemia (CML), TKIs have not fully cured CML due to TKI-resistant CML stem cells. Moreover, relapse after discontinuation of TKIs has not been predicted in CML patients with the best TKI response. In our study, a model of CML stem cells derived from CML induced pluripotent stem cells identified ADAM8 as an antigen of TKI-resistant CML cells. The inhibition of expression or metalloproteinase activity of ADAM8 restored TKI sensitivity in primary samples. In addition, residual CML cells in patients with optimal TKI response were concentrated in the ADAM8+ population. Our study demonstrates that ADAM8 is a marker of residual CML cells even in patients with optimal TKI response and would be a predictor of relapse and a therapeutic target of TKI-resistant CML cells.

Access to Document (DOI)

A novel genetic and morphologic phenotype of ARID2-mediated myelodysplasia

Sakai, H., Hosono, N., Nakazawa, H., Przychodzen, B., Polprasert, C., Carraway, H. E., Sekeres, M. A., Radivoyevitch, T., Yoshida, K., Sanada, M., Yoshizato, T., Kataoka, K., Nakagawa, M. M., Ueno, H., Nannya, Y., Kon, A., Shiozawa, Y., Takeda, J., Shiraishi, Y., Chiba, K., Miyano, S., Singh, J., Padgett, R. A., Ogawa, S., Maciejewski, J. P. and Makishima, H.

Leukemia 32 ( 3 ) 839 - 843 2018.03

ISSN 1476-5551

Access to Document (DOI)

Integrated Molecular Characterization of the Lethal Pediatric Cancer Pancreatoblastoma

Isobe, T., Seki, M., Yoshida, K., Sekiguchi, M., Shiozawa, Y., Shiraishi, Y., Kimura, S., Yoshida, M., Inoue, Y., Yokoyama, A., Kakiuchi, N., Suzuki, H., Kataoka, K., Sato, Y., Kawai, T., Chiba, K., Tanaka, H., Shimamura, T., Kato, M., Iguchi, A., Hama, A., Taguchi, T., Akiyama, M., Fujimura, J., Inoue, A., Ito, T., Deguchi, T., Kiyotani, C., Iehara, T., Hosoi, H., Oka, A., Sanada, M., Tanaka, Y., Hata, K., Miyano, S., Ogawa, S. and Takita, J.

Cancer Res 78 ( 4 ) 865 - 876 2018.02

ISSN 1538-7445

Pancreatoblastoma is a rare pediatric pancreatic malignancy for which the molecular pathogenesis is not understood. In this study, we report the findings of an integrated multiomics study of whole-exome and RNA sequencing as well as genome-wide copy number and methylation analyses of ten pancreatoblastoma cases. The pancreatoblastoma genome was characterized by a high frequency of aberrant activation of the Wnt signaling pathway, either via somatic mutations of CTNNB1 (90%) and copy-neutral loss of heterozygosity (CN-LOH) of APC (10%). In addition, imprinting dysregulation of IGF2 as a consequence of CN-LOH (80%), gain of paternal allele (10%), and gain of methylation (10%) was universally detected. At the transcriptome level, pancreatoblastoma exhibited an expression profile characteristic of early pancreas progenitor-like cells along with upregulation of the R-spondin/LGR5/RNF43 module. Our results offer a comprehensive description of the molecular basis for pancreatoblastoma and highlight rational therapeutic targets for its treatment.Significance: Molecular genetic analysis of a rare untreatable pediatric tumor reveals Wnt/IGF2 aberrations and features of early pancreas progenitor-like cells, suggesting cellular origins and rational strategies for therapeutic targeting. Cancer Res; 78(4); 865-76. (c)2017 AACR.

Access to Document (DOI)

Physiological Srsf2 P95H expression causes impaired hematopoietic stem cell functions and aberrant RNA splicing in mice

Kon, A., Yamazaki, S., Nannya, Y., Kataoka, K., Ota, Y., Nakagawa, M. M., Yoshida, K., Shiozawa, Y., Morita, M., Yoshizato, T., Sanada, M., Nakayama, M., Koseki, H., Nakauchi, H. and Ogawa, S.

Blood 131 ( 6 ) 621 - 635 2018.02

ISSN 1528-0020

Splicing factor mutations are characteristic of myelodysplastic syndromes (MDS) and related myeloid neoplasms and implicated in their pathogenesis, but their roles in the development of MDS have not been fully elucidated. In the present study, we investigated the consequence of mutant Srsf2 expression using newly generated Vav1-Cre-mediated conditional knockin mice. Mice carrying a heterozygous Srsf2 P95H mutation showed significantly reduced numbers of hematopoietic stem and progenitor cells (HSPCs) and differentiation defects both in the steady-state condition and transplantation settings. Srsf2-mutated hematopoietic stem cells (HSCs) showed impaired long-term reconstitution compared with control mice in competitive repopulation assays. Although the Srsf2 mutant mice did not develop MDS under the steady-state condition, when their stem cells were transplanted into lethally irradiated mice, the recipients developed anemia, leukopenia, and erythroid dysplasia, which suggests the role of replicative stress in the development of an MDS-like phenotype in Srsf2-mutated mice. RNA sequencing of the Srsf2-mutated HSPCs revealed a number of abnormal splicing events and differentially expressed genes, including several potential targets implicated in the pathogenesis of hematopoietic malignancies, such as Csf3r, Fyn, Gnas, Nsd1, Hnrnpa2b1, and Trp53bp1 Among the mutant Srsf2-associated splicing events, most commonly observed were the enhanced inclusion and/or exclusion of cassette exons, which were caused by the altered consensus motifs for the recognition of exonic splicing enhancers. Our findings suggest that the mutant Srsf2 leads to a compromised HSC function by causing abnormal RNA splicing and expression, contributing to the deregulated hematopoiesis that recapitulates the MDS phenotypes, possibly as a result of additional genetic and/or environmental insults.

Access to Document (DOI)

Prognostic relevance of integrated genetic profiling in adult T-cell leukemia/lymphoma

Kataoka, K., Iwanaga, M., Yasunaga, J. I., Nagata, Y., Kitanaka, A., Kameda, T., Yoshimitsu, M., Shiraishi, Y., Sato-Otsubo, A., Sanada, M., Chiba, K., Tanaka, H., Ochi, Y., Aoki, K., Suzuki, H., Shiozawa, Y., Yoshizato, T., Sato, Y., Yoshida, K., Nosaka, K., Hishizawa, M., Itonaga, H., Imaizumi, Y., Munakata, W., Shide, K., Kubuki, Y., Hidaka, T., Nakamaki, T., Ishiyama, K., Miyawaki, S., Ishii, R., Nureki, O., Tobinai, K., Miyazaki, Y., Takaori-Kondo, A., Shibata, T., Miyano, S., Ishitsuka, K., Utsunomiya, A., Shimoda, K., Matsuoka, M., Watanabe, T. and Ogawa, S.

Blood 131 ( 2 ) 215 - 225 2018.01

ISSN 1528-0020

Adult T-cell leukemia/lymphoma (ATL) is a heterogeneous group of peripheral T-cell malignancies characterized by human T-cell leukemia virus type-1 infection, whose genetic profile has recently been fully investigated. However, it is still poorly understood how these alterations affect clinical features and prognosis. We investigated the effects of genetic alterations commonly found in ATL on disease phenotypes and clinical outcomes, based on genotyping data obtained from 414 and 463 ATL patients using targeted-capture sequencing and single nucleotide polymorphism array karyotyping, respectively. Aggressive (acute/lymphoma) subtypes were associated with an increased burden of genetic and epigenetic alterations, higher frequencies of TP53 and IRF4 mutations, and many copy number alterations (CNAs), including PD-L1 amplifications and CDKN2A deletions, compared with indolent (chronic/smoldering) subtypes. By contrast, STAT3 mutations were more characteristic of indolent ATL. Higher numbers of somatic mutations and CNAs significantly correlated with worse survival. In a multivariate analysis incorporating both clinical factors and genetic alterations, the Japan Clinical Oncology Group prognostic index high-risk, older age, PRKCB mutations, and PD-L1 amplifications were independent poor prognostic factors in aggressive ATL. In indolent ATL, IRF4 mutations, PD-L1 amplifications, and CDKN2A deletions were significantly associated with shorter survival, although the chronic subtype with unfavorable clinical factors was only marginally significant. Thus, somatic alterations characterizing aggressive diseases predict worse prognosis in indolent ATL, among which PD-L1 amplifications are a strong genetic predictor in both aggressive and indolent ATL. ATL subtypes are further classified into molecularly distinct subsets with different prognosis. Genetic profiling might contribute to improved prognostication and management of ATL patients.

Access to Document (DOI)

Prognostic relevance of genetic alterations in diffuse lower-grade gliomas

Aoki, K., Nakamura, H., Suzuki, H., Matsuo, K., Kataoka, K., Shimamura, T., Motomura, K., Ohka, F., Shiina, S., Yamamoto, T., Nagata, Y., Yoshizato, T., Mizoguchi, M., Abe, T., Momii, Y., Muragaki, Y., Watanabe, R., Ito, I., Sanada, M., Yajima, H., Morita, N., Takeuchi, I., Miyano, S., Wakabayashi, T., Ogawa, S. and Natsume, A.

Neuro Oncol 20 ( 1 ) 66 - 77 2018.01

ISSN 1523-5866

Background: Diffuse lower-grade gliomas (LGGs) are genetically classified into 3 distinct subtypes based on isocitrate dehydrogenase (IDH) mutation status and codeletion of chromosome 1p and 19q (1p/19q). However, the subtype-specific effects of additional genetic lesions on survival are largely unknown. Methods: Using Cox proportional hazards regression modeling, we investigated the subtype-specific effects of genetic alterations and clinicopathological factors on survival in each LGG subtype, in a Japanese cohort of LGG cases fully genotyped for driver mutations and copy number variations associated with LGGs (n = 308). The results were validated using a dataset from 414 LGG cases available from The Cancer Genome Atlas (TCGA). Results: In Oligodendroglioma, IDH-mutant and 1p/19q codeleted, NOTCH1 mutations (P = 0.0041) and incomplete resection (P = 0.0019) were significantly associated with shorter survival. In Astrocytoma, IDH-mutant, PIK3R1 mutations (P = 0.0014) and altered retinoblastoma pathway genes (RB1, CDKN2A, and CDK4) (P = 0.013) were independent predictors of poor survival. In IDH-wildtype LGGs, co-occurrence of 7p gain, 10q loss, mutation in the TERT promoter (P = 0.024), and grade III histology (P < 0.0001) independently predicted poor survival. IDH-wildtype LGGs without any of these factors were diagnosed at a younger age (P = 0.042), and were less likely to have genetic lesions characteristic of glioblastoma, in comparison with other IDH-wildtype LGGs, suggesting that they likely represented biologically different subtypes. These results were largely confirmed in the cohort of TCGA. Conclusions: Subtype-specific genetic lesions can be used to stratify patients within each LGG subtype. enabling better prognostication and management.

Access to Document (DOI)

Identification of the genetic and clinical characteristics of neuroblastomas using genome-wide analysis

Uryu, K., Nishimura, R., Kataoka, K., Sato, Y., Nakazawa, A., Suzuki, H., Yoshida, K., Seki, M., Hiwatari, M., Isobe, T., Shiraishi, Y., Chiba, K., Tanaka, H., Miyano, S., Koh, K., Hanada, R., Oka, A., Hayashi, Y., Ohira, M., Kamijo, T., Nagase, H., Takimoto, T., Tajiri, T., Nakagawara, A., Ogawa, S. and Takita, J.

Oncotarget 8 ( 64 ) 107513 - 107529 2017.12

ISSN 1949-2553

To provide better insight into the genetic signatures of neuroblastomas, we analyzed 500 neuroblastomas (included specimens from JNBSG) using targeted-deep sequencing for 10 neuroblastoma-related genes and SNP arrays analysis. ALK expression was evaluated using immunohistochemical analysis in 259 samples. Based on genetic alterations, the following 6 subgroups were identified: groups A (ALK abnormalities), B (other gene mutations), C (MYCN amplification), D (11q loss of heterozygosity [LOH]), E (at least 1 copy number variants), and F (no genetic changes). Groups A to D showed advanced disease and poor prognosis, whereas groups E and F showed excellent prognosis. Intriguingly, in group A, MYCN amplification was not a significant prognostic marker, while high ALK expression was a relevant indicator for prognosis (P = 0.033). Notably, the co-existence of MYCN amplification and 1p LOH, and the co-deletion of 3p and 11q were significant predictors of relapse (P = 0.043 and P = 0.040). Additionally, 6q/8p LOH and 17q gain were promising indicators of survival in patients older than 5 years, and 1p, 4p, and 11q LOH potentially contributed to outcome prediction in the intermediate-risk group. Our genetic overview clarifies the clinical impact of genetic signatures and aids in the better understanding of genetic basis of neuroblastoma.

Access to Document (DOI)

A Cryptic NUP214-ABL1 Fusion in B-cell Precursor Acute Lymphoblastic Leukemia

Tsujimoto, S. I., Nakano, Y., Osumi, T., Okada, K., Ouchi-Uchiyama, M., Kataoka, K., Fujii, Y., Ohki, K., Seki, M., Tamagawa, N., Takita, J., Ogawa, S., Kiyokawa, N., Hara, J. and Kato, M.

J Pediatr Hematol Oncol 2017.12

ISSN 1536-3678

Fluorescent in situ hybridization (FISH) analysis is the standard methods for screening ABL1 fusions, which is recurrently translocated in pediatric acute lymphoblastic leukemia (ALL), and potentially targetable by kinase inhibitors. Here we demonstrated a case of B-cell precursor ALL with NUP214-ABL1 fusion, which break-apart FISH assay for ABL1 failed to detect. The cryptic fusion was generated by small duplication from ABL1 to NUP214, which was detected by copy number analysis using genomic microarray and confirmed by PCR. In the context of precision medicine, we should establish how to screen targetable abnormalities for minimizing risk of false-negative.

Access to Document (DOI)

Loss of DNA Damage Response in Neuroblastoma and Utility of a PARP Inhibitor

Takagi, M., Yoshida, M., Nemoto, Y., Tamaichi, H., Tsuchida, R., Seki, M., Uryu, K., Nishii, R., Miyamoto, S., Saito, M., Hanada, R., Kaneko, H., Miyano, S., Kataoka, K., Yoshida, K., Ohira, M., Hayashi, Y., Nakagawara, A., Ogawa, S., Mizutani, S. and Takita, J.

J Natl Cancer Inst 109 ( 11 ) 2017.11

ISSN 1460-2105

Background: Neuroblastoma (NB) is the most common solid tumor found in children, and deletions within the 11q region are observed in 11% to 48% of these tumors. Notably, such tumors are associated with poor prognosis; however, little is known regarding the molecular targets located in 11q. Methods: Genomic alterations of ATM , DNA damage response (DDR)-associated genes located in 11q ( MRE11A, H2AFX , and CHEK1 ), and BRCA1, BARD1, CHEK2, MDM2 , and TP53 were investigated in 45 NB-derived cell lines and 237 fresh tumor samples. PARP (poly [ADP-ribose] polymerase) inhibitor sensitivity of NB was investigated in in vitro and invivo xenograft models. All statistical tests were two-sided. Results: Among 237 fresh tumor samples, ATM, MRE11A, H2AFX , and/or CHEK1 loss or imbalance in 11q was detected in 20.7% of NBs, 89.8% of which were stage III or IV. An additional 7.2% contained ATM rare single nucleotide variants (SNVs). Rare SNVs in DDR-associated genes other than ATM were detected in 26.4% and were mutually exclusive. Overall, samples with SNVs and/or copy number alterations in these genes accounted for 48.4%. ATM-defective cells are known to exhibit dysfunctions in homologous recombination repair, suggesting a potential for synthetic lethality by PARP inhibition. Indeed, 83.3% NB-derived cell lines exhibited sensitivity to PARP inhibition. In addition, NB growth was markedly attenuated in the xenograft group receiving PARP inhibitors (sham-treated vs olaprib-treated group; mean [SD] tumor volume of sham-treated vs olaprib-treated groups = 7377 [1451] m 3 vs 298 [312] m 3 , P = .001, n = 4). Conclusions: Genomic alterations of DDR-associated genes including ATM, which regulates homologous recombination repair, were observed in almost half of NBs, suggesting that synthetic lethality could be induced by treatment with a PARP inhibitor. Indeed, DDR-defective NB cell lines were sensitive to PARP inhibitors. Thus, PARP inhibitors represent candidate NB therapeutics.

Access to Document (DOI)

Genetic alterations in adult T-cell leukemia/lymphoma

Kogure, Y. and Kataoka, K.

Cancer Sci 108 ( 9 ) 1719 - 1725 2017.09

ISSN 1349-7006

Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell neoplasm with a dismal prognosis. It is caused by human T-cell leukemia virus type-1 (HTLV-1) retrovirus. A long latency period from HTLV-1 infection to ATL onset suggests that not only HTLV-1 proteins, such as Tax and HBZ, but also additional genetic and/or epigenetic events are required for ATL development. Although many studies have demonstrated the biological functions of viral genes, alterations of cellular genes associated with ATL have not been fully investigated. Recently, a large-scale integrated genetic analysis revealed the entire landscape of somatic aberrations in ATL. This neoplasm is characterized by frequent gain-of-function alterations in components of the T-cell receptor/NF-kappaB signaling pathway, including activating mutations in the PLCG1, PRKCB, CARD11 and VAV1 genes, and CTLA4-CD28 and ICOS-CD28 fusions. Importantly, molecules associated with immune surveillance, such as HLA-A/B, CD58 and FAS, are affected recurrently. Among them, one notable lesion occurs as frequent structural variations that truncate the PD-L1 3'-untranslated region, leading to its overexpression. Other genetic targets include transcription factors (IRF4, IKZF2, and GATA3) and chemokine receptors (CCR4, CCR7 and GPR183), which are functionally relevant in normal T cells. A substantial proportion of ATL cases show widespread accumulation of repressive epigenetic changes, such as trimethylation of histone H3 lysine 27 and DNA hypermethylation of CpG islands, which coordinately modulate multiple pathways, including Cys2-His2 zinc finger genes involved in silencing retroelements. Here we review the current understanding of the genetic/epigenetic aberrations in ATL, focusing on their relevance in its molecular pathogenesis.

Access to Document (DOI)

Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia

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. and Takita, J.

Nat Genet 49 ( 8 ) 1274 - 1281 2017.08

ISSN 1546-1718

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-beta-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.

Access to Document (DOI)

Loss of p53 induces leukemic transformation in a murine model of Jak2 V617F-driven polycythemia vera

Tsuruta-Kishino, T., Koya, J., Kataoka, K., Narukawa, K., Sumitomo, Y., Kobayashi, H., Sato, T. and Kurokawa, M.

Oncogene 36 ( 23 ) 3300 - 3311 2017.06

ISSN 1476-5594

As leukemic transformation of myeloproliferative neoplasms (MPNs) worsens the clinical outcome, reducing the inherent risk of the critical event in MPN cases could be beneficial. Among genetic alterations concerning the transformation, the frequent one is TP53 mutation. Here we show that retroviral overexpression of Jak2 V617F mutant into wild-type p53 murine bone marrow cells induced polycythemia vera (PV) in the recipient mice, whereas Jak2 V617F-transduced p53-null mice developed lethal leukemia after the preceding PV phase. The leukemic mice had severe anemia, hepatosplenomegaly, pulmonary hemorrhage and expansion of dysplastic erythroid progenitors. Primitive leukemia cells (c-kit(+)Sca1(+)Lin(-) (KSL) and CD34(-)CD16/32(-)c-kit(+)Sca1(-)Lin(-) (megakaryocyte-erythroid progenitor; MEP)) and erythroid progenitors (CD71(+)) from Jak2 V617F-transduced p53-null leukemic mice had leukemia-initiating capacity, however, myeloid differentiated populations (Mac-1(+)) could not recapitulate the disease. Interestingly, recipients transplanted with CD71(+) cells rapidly developed erythroid leukemia, which was in sharp contrast to leukemic KSL cells to cause lethal leukemia after the polycythemic state. The leukemic CD71(+) cells were more sensitive to INCB18424, a potent JAK inhibitor, than KSL cells. p53 restoration could ameliorate Jak2 V617F-transduced p53-null erythroleukemia. Taken together, our results show that p53 loss is sufficient for inducing leukemic transformation in Jak2 V617F-positive MPN.

Access to Document (DOI)

A TLR3-Specific Adjuvant Relieves Innate Resistance to PD-L1 Blockade without Cytokine Toxicity in Tumor Vaccine Immunotherapy

Takeda, Y., Kataoka, K., Yamagishi, J., Ogawa, S., Seya, T. and Matsumoto, M.

Cell Rep 19 ( 9 ) 1874 - 1887 2017.05

ISSN 2211-1247

Cancer patients having anti-programmed cell death-1 (PD-1)/PD ligand 1 (L1)-unresponsive tumors may benefit from advanced immunotherapy. Double-stranded RNA triggers dendritic cell (DC) maturation to cross-prime antigen-specific cytotoxic T lymphocytes (CTLs) via Toll-like receptor 3 (TLR3). The TLR3-specific RNA agonist, ARNAX, can induce anti-tumor CTLs without systemic cytokine/interferon (IFN) production. Here, we have developed a safe vaccine adjuvant for cancer that effectively implements anti-PD-L1 therapy. Co-administration of ARNAX with a tumor-associated antigen facilitated tumor regression in mouse models, and in combination with anti-PD-L1 antibody, activated tumor-specific CTLs in lymphoid tissues, enhanced CTL infiltration, and overcame anti-PD-1 resistance without cytokinemia. The TLR3-TICAM-1-interferon regulatory factor (IRF)3-IFN-beta axis in DCs exclusively participated in CD8+ T cell cross-priming. ARNAX therapy established Th1 immunity in the tumor microenvironment, upregulating genes involved in DC/T cell/natural killer (NK) cell recruitment and functionality. Human ex vivo studies disclosed that ARNAX+antigen induced antigen-specific CTL priming and proliferation in peripheral blood mononuclear cells (PBMCs), supporting the feasibility of ARNAX for potentiating anti-PD-1/PD-L1 therapy in human vaccine immunotherapy.

Access to Document (DOI)

Constitutional abnormalities of IDH1 combined with secondary mutations predispose a patient with Maffucci syndrome to acute lymphoblastic leukemia

Hirabayashi, S., Seki, M., Hasegawa, D., Kato, M., Hyakuna, N., Shuo, T., Kimura, S., Yoshida, K., Kataoka, K., Fujii, Y., Shiraishi, Y., Chiba, K., Tanaka, H., Kiyokawa, N., Miyano, S., Ogawa, S., Takita, J. and Manabe, A.

Pediatr Blood Cancer 2017.05

ISSN 1545-5017

Maffucci syndrome is a nonhereditary disorder caused by somatic mosaic isocitrate dehydrogenase 1 or 2 (IDH1 or IDH2) mutations and is characterized by multiple enchondromas along with hemangiomas. Malignant transformation of enchondromas to chondrosarcomas and secondary neoplasms, such as brain tumors or acute myeloid leukemia, are serious complications. A 15-year-old female with Maffucci syndrome developed B-cell precursor acute lymphoblastic leukemia (BCP-ALL). A somatic mutation in IDH1 was detected in hemangioma and leukemic cells. KRAS mutation and deletion of IKZF1 were detected in leukemic cells. Patients with Maffucci syndrome may, therefore, be at risk of BCP-ALL associated with secondary genetic events that affect lymphocyte differentiation.

Access to Document (DOI)

Genetic abnormalities in myelodysplasia and secondary acute myeloid leukemia: impact on outcome of stem cell transplantation

Yoshizato, T., Nannya, Y., Atsuta, Y., Shiozawa, Y., Iijima-Yamashita, Y., Yoshida, K., Shiraishi, Y., Suzuki, H., Nagata, Y., Sato, Y., Kakiuchi, N., Matsuo, K., Onizuka, M., Kataoka, K., Chiba, K., Tanaka, H., Ueno, H., Nakagawa, M. M., Przychodzen, B., Haferlach, C., Kern, W., Aoki, K., Itonaga, H., Kanda, Y., Sekeres, M. A., Maciejewski, J. P., Haferlach, T., Miyazaki, Y., Horibe, K., Sanada, M., Miyano, S., Makishima, H. and Ogawa, S.

Blood 129 ( 17 ) 2347 - 2358 2017.04

ISSN 1528-0020

Genetic alterations, including mutations and copy-number alterations, are central to the pathogenesis of myelodysplastic syndromes and related diseases (myelodysplasia), but their roles in allogeneic stem cell transplantation have not fully been studied in a large cohort of patients. We enrolled 797 patients who had been diagnosed with myelodysplasia at initial presentation and received transplantation via the Japan Marrow Donor Program. Targeted-capture sequencing was performed to identify mutations in 69 genes, together with copy-number alterations, whose effects on transplantation outcomes were investigated. We identified 1776 mutations and 927 abnormal copy segments among 617 patients (77.4%). In multivariate modeling using Cox proportional-hazards regression, genetic factors explained 30% of the total hazards for overall survival; clinical characteristics accounted for 70% of risk. TP53 and RAS-pathway mutations, together with complex karyotype (CK) as detected by conventional cytogenetics and/or sequencing-based analysis, negatively affected posttransplant survival independently of clinical factors. Regardless of disease subtype, TP53-mutated patients with CK were characterized by unique genetic features and associated with an extremely poor survival with frequent early relapse, whereas outcomes were substantially better in TP53-mutated patients without CK. By contrast, the effects of RAS-pathway mutations depended on disease subtype and were confined to myelodysplastic/myeloproliferative neoplasms (MDS/MPNs). Our results suggest that TP53 and RAS-pathway mutations predicted a dismal prognosis, when associated with CK and MDS/MPNs, respectively. However, for patients with mutated TP53 or CK alone, long-term survival could be obtained with transplantation. Clinical sequencing provides vital information for accurate prognostication in transplantation.

Access to Document (DOI)

Blastic transformation of juvenile myelomonocytic leukemia caused by the copy number gain of oncogenic KRAS

Osumi, T., Kato, M., Ouchi-Uchiyama, M., Tomizawa, D., Kataoka, K., Fujii, Y., Seki, M., Takita, J., Ogawa, S., Uchiyama, T., Ohki, K. and Kiyokawa, N.

Pediatr Blood Cancer 2017.02

ISSN 1545-5017

Previous studies have reported several cases of juvenile myelomonocytic leukemia (JMML) developing blastic transformation during an indolent clinical course, but the underlying mechanism of transformation is still not well understood. In this report, we describe a case of JMML with blastic transformation possibly caused by additional copy number gains of the KRAS mutant allele. We have discovered that the copy number gain of the mutant allele is an additional possible cause of blastic transformation in JMML.

Access to Document (DOI)

Regeneration of CD8alphabeta T Cells from T-cell-Derived iPSC Imparts Potent Tumor Antigen-Specific Cytotoxicity

Maeda, T., Nagano, S., Ichise, H., Kataoka, K., Yamada, D., Ogawa, S., Koseki, H., Kitawaki, T., Kadowaki, N., Takaori-Kondo, A., Masuda, K. and Kawamoto, H.

Cancer Res 76 ( 23 ) 6839 - 6850 2016.12

ISSN 1538-7445

Although adoptive transfer of cytotoxic T lymphocytes (CTL) offer a promising cancer therapeutic direction, the generation of antigen-specific CTL from patients has faced difficulty in efficient expansion in ex vivo culture. To resolve this issue, several groups have proposed that induced pluripotent stem cell technology be applied for the expansion of antigen-specific CTL, which retain expression of the same T-cell receptor as original CTL. However, in these previous studies, the regenerated CTL are mostly of the CD8alphaalpha+ innate type and have less antigen-specific cytotoxic activity than primary CTL. Here we report that, by stimulating purified iPSC-derived CD4/CD8 double-positive cells with anti-CD3 antibody, T cells expressing CD8alphabeta were generated and exhibited improved antigen-specific cytotoxicity compared with CD8alphaalpha+ CTL. Failure of CD8alphabeta T-cell production using the previous method was found to be due to killing of double-positive cells by the double-negative cells in the mixed cultures. We found that WT1 tumor antigen-specific CTL regenerated by this method prolonged the survival of mice bearing WT1-expressing leukemic cells. Implementation of our methods may offer a useful clinical tool. Cancer Res; 76(23); 6839-50. (c)2016 AACR.

Access to Document (DOI)

　 Previous page - Next page 　