Details of a Researcher - Kataoka, Keisuke

Papers - Kataoka, Keisuke

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Variegated RHOA mutations in human cancers

Kataoka, K. and Ogawa, S.

Exp Hematol 44 ( 12 ) 1123 - 1129 2016.12

ISSN 1873-2399

RHOA is one of the most extensively investigated members of the Rho GTPase family of proteins and has long been implicated in malignant transformation as well as tumor invasion and metastasis. Recently, revolutionized sequencing platforms have revealed frequent RHOA mutations in a wide variety of human cancers, including angio-immunoblastic T-cell lymphoma, adult T-cell leukemia/lymphoma, germinal center B-cell lymphoma, diffuse-type gastric cancer, and other solid tumors. With their discrete positional distributions and types of amino acid substitution depending on cancer type, different RHOA mutations seem to have unique functional and biological properties. However, their impact on the development of different types of tumors remains controversial. Here, we present an overview of the current understanding of RHOA mutations in human cancers and highlight the unanticipated complexity of their genetic and biological properties.

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Somatic PHF6 mutations in 1760 cases with various myeloid neoplasms

Mori, T., Nagata, Y., Makishima, H., Sanada, M., Shiozawa, Y., Kon, A., Yoshizato, T., Sato-Otsubo, A., Kataoka, K., Shiraishi, Y., Chiba, K., Tanaka, H., Ishiyama, K., Miyawaki, S., Mori, H., Nakamaki, T., Kihara, R., Kiyoi, H., Koeffler, H. P., Shih, L. Y., Miyano, S., Naoe, T., Haferlach, C., Kern, W., Haferlach, T., Ogawa, S. and Yoshida, K.

Leukemia 30 ( 11 ) 2270 - 2273 2016.11

ISSN 1476-5551

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Cytoprotective autophagy maintains leukemia-initiating cells in murine myeloid leukemia

Sumitomo, Y., Koya, J., Nakazaki, K., Kataoka, K., Tsuruta-Kishino, T., Morita, K., Sato, T. and Kurokawa, M.

Blood 128 ( 12 ) 1614 - 24 2016.09

ISSN 1528-0020

Despite advances in the treatment of acute myeloid leukemia (AML), relapse and drug resistance frequently occur. Therefore, detailed mechanisms of refractoriness, including leukemia-initiating cell (LIC) biology, should be elucidated to treat AML. The self-degradative property of cytosolic macromolecules is central to autophagy and can contribute to homeostasis and stress response. Recent reports suggest the importance of autophagy in hematopoietic stem cells and various tumors. Thus, this study investigated the functional role of autophagy in AML maintenance and drug resistance using tamoxifen-inducible conditional knockout mice of Atg5 or Atg7, which are essential genes for autophagy, combined with an mixed lineage leukemia-eleven nineteen leukemia-induced murine AML model. Inactivation of autophagy by deletion of Atg5 or Atg7 prolonged survival in leukemic mice and reduced functional LICs. Atg7-deficient LICs displayed enhanced mitochondrial activity and reactive oxygen species production together with increased cell death. In addition, Atg7 deletion markedly decreased peripheral blood leukemia cells, concurrent with increased apoptosis, suggesting a higher dependency on autophagy compared with bone marrow leukemia cells. Finally, cytarabine (AraC) treatment activated autophagy in LICs, and Atg7 deletion potentiated the therapeutic effects of AraC, which included decreased LICs and prolonged survival, suggesting that autophagy contributes to AraC resistance. Our results highlight the intratumoral heterogeneity related to autophagy in AML and the unique role of autophagy in leukemia development and drug resistance.

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Aberrant PD-L1 expression through 3'-UTR disruption in multiple cancers

Kataoka, K., Shiraishi, Y., Takeda, Y., Sakata, S., Matsumoto, M., Nagano, S., Maeda, T., Nagata, Y., Kitanaka, A., Mizuno, S., Tanaka, H., Chiba, K., Ito, S., Watatani, Y., Kakiuchi, N., Suzuki, H., Yoshizato, T., Yoshida, K., Sanada, M., Itonaga, H., Imaizumi, Y., Totoki, Y., Munakata, W., Nakamura, H., Hama, N., Shide, K., Kubuki, Y., Hidaka, T., Kameda, T., Masuda, K., Minato, N., Kashiwase, K., Izutsu, K., Takaori-Kondo, A., Miyazaki, Y., Takahashi, S., Shibata, T., Kawamoto, H., Akatsuka, Y., Shimoda, K., Takeuchi, K., Seya, T., Miyano, S. and Ogawa, S.

Nature 534 ( 7607 ) 402 - 6 2016.06

ISSN 1476-4687

Successful treatment of many patients with advanced cancer using antibodies against programmed cell death 1 (PD-1; also known as PDCD1) and its ligand (PD-L1; also known as CD274) has highlighted the critical importance of PD-1/PD-L1-mediated immune escape in cancer development. However, the genetic basis for the immune escape has not been fully elucidated, with the exception of elevated PD-L1 expression by gene amplification and utilization of an ectopic promoter by translocation, as reported in Hodgkin and other B-cell lymphomas, as well as stomach adenocarcinoma. Here we show a unique genetic mechanism of immune escape caused by structural variations (SVs) commonly disrupting the 3' region of the PD-L1 gene. Widely affecting multiple common human cancer types, including adult T-cell leukaemia/lymphoma (27%), diffuse large B-cell lymphoma (8%), and stomach adenocarcinoma (2%), these SVs invariably lead to a marked elevation of aberrant PD-L1 transcripts that are stabilized by truncation of the 3'-untranslated region (UTR). Disruption of the Pd-l1 3'-UTR in mice enables immune evasion of EG7-OVA tumour cells with elevated Pd-l1 expression in vivo, which is effectively inhibited by Pd-1/Pd-l1 blockade, supporting the role of relevant SVs in clonal selection through immune evasion. Our findings not only unmask a novel regulatory mechanism of PD-L1 expression, but also suggest that PD-L1 3'-UTR disruption could serve as a genetic marker to identify cancers that actively evade anti-tumour immunity through PD-L1 overexpression.

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Paroxysmal nocturnal hemoglobinuria induced by the occurrence of BCR-ABL in a PIGA mutant hematopoietic progenitor cell

Tominaga, R., Katagiri, T., Kataoka, K., Kataoka, K., Wee, R. K., Maeda, A., Gomyo, H., Mizuno, I., Murayama, T., Ogawa, S. and Nakao, S.

Leukemia 30 ( 5 ) 1208 - 10 2016.05

ISSN 1476-5551

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Mutational Landscape and Antiproliferative Functions of ELF Transcription Factors in Human Cancer

Ando, M., Kawazu, M., Ueno, T., Koinuma, D., Ando, K., Koya, J., Kataoka, K., Yasuda, T., Yamaguchi, H., Fukumura, K., Yamato, A., Soda, M., Sai, E., Yamashita, Y., Asakage, T., Miyazaki, Y., Kurokawa, M., Miyazono, K., Nimer, S. D., Yamasoba, T. and Mano, H.

Cancer Res 76 ( 7 ) 1814 - 24 2016.04

ISSN 1538-7445

ELF4 (also known as MEF) is a member of the ETS family of transcription factors. An oncogenic role for ELF4 has been demonstrated in hematopoietic malignancies, but its function in epithelial tumors remains unclear. Here, we show that ELF4 can function as a tumor suppressor and is somatically inactivated in a wide range of human tumors. We identified a missense mutation affecting the transactivation potential of ELF4 in oral squamous cell carcinoma cells. Restoration of the transactivation activity through introduction of wild-type ELF4 significantly inhibited cell proliferation in vitro and tumor xenograft growth. Furthermore, we found that ELF1 and ELF2, closely related transcription factors to ELF4, also exerted antiproliferative effects in multiple cancer cell lines. Mutations in ELF1 and ELF2, as in ELF4, were widespread across human cancers, but were almost all mutually exclusive. Moreover, chromatin immunoprecipitation coupled with high-throughput sequencing revealed ELF4-binding sites in genomic regions adjacent to genes related to cell-cycle regulation and apoptosis. Finally, we provide mechanistic evidence that the antiproliferative effects of ELF4 were mediated through the induction of HRK, an activator of apoptosis, and DLX3, an inhibitor of cell growth. Collectively, our findings reveal a novel subtype of human cancer characterized by inactivating mutations in the ELF subfamily of proteins, and warrant further investigation of the specific settings where ELF restoration may be therapeutically beneficial. Cancer Res; 76(7); 1814-24. (c)2016 AACR.

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DNMT3A R882 mutants interact with polycomb proteins to block haematopoietic stem and leukaemic cell differentiation

Koya, J., Kataoka, K., Sato, T., Bando, M., Kato, Y., Tsuruta-Kishino, T., Kobayashi, H., Narukawa, K., Miyoshi, H., Shirahige, K. and Kurokawa, M.

Nat Commun 7 10924 2016.03

ISSN 2041-1723

Despite the clinical impact of DNMT3A mutation on acute myeloid leukaemia, the molecular mechanisms regarding how this mutation causes leukaemogenesis in vivo are largely unknown. Here we show that, in murine transplantation experiments, recipients transplanted with DNMT3A mutant-transduced cells exhibit aberrant haematopoietic stem cell (HSC) accumulation. Differentiation-associated genes are downregulated without accompanying changes in methylation status of their promoter-associated CpG islands in DNMT3A mutant-transduced stem/progenitor cells, representing a DNA methylation-independent role of mutated DNMT3A. DNMT3A R882H also promotes monoblastic transformation in vitro in combination with HOXA9. Molecularly, the DNMT3A mutant interacts with polycomb repressive complex 1 (PRC1), causing transcriptional silencing, revealing a DNA methylation-independent role of DNMT3A mutation. Suppression of PRC1 impairs aberrant HSC accumulation and monoblastic transformation. From our data, it is shown that DNMT3A mutants can block the differentiation of HSCs and leukaemic cells via PRC1. This interaction could be targetable in DNMT3A-mutated leukaemias.

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Variegated RHOA mutations in adult T-cell leukemia/lymphoma

Nagata, Y., Kontani, K., Enami, T., Kataoka, K., Ishii, R., Totoki, Y., Kataoka, T. R., Hirata, M., Aoki, K., Nakano, K., Kitanaka, A., Sakata-Yanagimoto, M., Egami, S., Shiraishi, Y., Chiba, K., Tanaka, H., Shiozawa, Y., Yoshizato, T., Suzuki, H., Kon, A., Yoshida, K., Sato, Y., Sato-Otsubo, A., Sanada, M., Munakata, W., Nakamura, H., Hama, N., Miyano, S., Nureki, O., Shibata, T., Haga, H., Shimoda, K., Katada, T., Chiba, S., Watanabe, T. and Ogawa, S.

Blood 127 ( 5 ) 596 - 604 2016.02

ISSN 1528-0020

Adult T-cell leukemia/lymphoma (ATLL) is a distinct form of peripheral T-cell lymphoma with poor prognosis, which is caused by the human T-lymphotropic virus type 1 (HTLV-1). In contrast to the unequivocal importance of HTLV-1 infection in the pathogenesis of ATLL, the role of acquired mutations in HTLV-1 infected T cells has not been fully elucidated, with a handful of genes known to be recurrently mutated. In this study, we identified unique RHOA mutations in ATLL through whole genome sequencing of an index case, followed by deep sequencing of 203 ATLL samples. RHOA mutations showed distinct distribution and function from those found in other cancers. Involving 15% (30/203) of ATLL cases, RHOA mutations were widely distributed across the entire coding sequence but almost invariably located at the guanosine triphosphate (GTP)-binding pocket, with Cys16Arg being most frequently observed. Unexpectedly, depending on mutation types and positions, these RHOA mutants showed different or even opposite functional consequences in terms of GTP/guanosine diphosphate (GDP)-binding kinetics, regulation of actin fibers, and transcriptional activation. The Gly17Val mutant did not bind GTP/GDP and act as a dominant negative molecule, whereas other mutants (Cys16Arg and Ala161Pro) showed fast GTP/GDP cycling with enhanced transcriptional activation. These findings suggest that both loss- and gain-of-RHOA functions could be involved in ATLL leukemogenesis. In summary, our study not only provides a novel insight into the molecular pathogenesis of ATLL but also highlights a unique role of variegation of heterologous RHOA mutations in human cancers.

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Genetic biomarkers for PD-1/PD-L1 blockade therapy

Kataoka, Keisuke and Ogawa, Seishi

Oncoscience 3 ( 11-12 ) 311 2016

BAALC potentiates oncogenic ERK pathway through interactions with MEKK1 and KLF4

Morita, K., Masamoto, Y., Kataoka, K., Koya, J., Kagoya, Y., Yashiroda, H., Sato, T., Murata, S. and Kurokawa, M.

Leukemia 29 ( 11 ) 2248 - 56 2015.11

ISSN 1476-5551

Although high brain and acute leukemia, cytoplasmic (BAALC) expression is a well-characterized poor prognostic factor in acute myeloid leukemia (AML), neither the exact mechanisms by which BAALC drives leukemogenesis and drug resistance nor therapeutic approaches against BAALC-high AML have been properly elucidated. In this study, we found that BAALC induced cell-cycle progression of leukemia cells by sustaining extracellular signal-regulated kinase (ERK) activity through an interaction with a scaffold protein MEK kinase-1 (MEKK1), which inhibits the interaction between ERK and MAP kinase phosphatase 3 (MKP3/DUSP6). BAALC conferred chemoresistance in AML cells by upregulating ATP-binding cassette proteins in an ERK-dependent manner, which can be therapeutically targeted by MEK inhibitor. We also demonstrated that BAALC blocks ERK-mediated monocytic differentiation of AML cells by trapping Kruppel-like factor 4 (KLF4) in the cytoplasm and inhibiting its function in the nucleus. Consequently, MEK inhibition therapy synergizes with KLF4 induction and is highly effective against BAALC-high AML cells both in vitro and in vivo. Our data provide a molecular basis for the role of BAALC in regulating proliferation and differentiation of AML cells and highlight the unique dual function of BAALC as an attractive therapeutic target against BAALC-high AML.

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Integrated molecular analysis of adult T cell leukemia/lymphoma

Kataoka, K., Nagata, Y., Kitanaka, A., Shiraishi, Y., Shimamura, T., Yasunaga, J., Totoki, Y., Chiba, K., Sato-Otsubo, A., Nagae, G., Ishii, R., Muto, S., Kotani, S., Watatani, Y., Takeda, J., Sanada, M., Tanaka, H., Suzuki, H., Sato, Y., Shiozawa, Y., Yoshizato, T., Yoshida, K., Makishima, H., Iwanaga, M., Ma, G., Nosaka, K., Hishizawa, M., Itonaga, H., Imaizumi, Y., Munakata, W., Ogasawara, H., Sato, T., Sasai, K., Muramoto, K., Penova, M., Kawaguchi, T., Nakamura, H., Hama, N., Shide, K., Kubuki, Y., Hidaka, T., Kameda, T., Nakamaki, T., Ishiyama, K., Miyawaki, S., Yoon, S. S., Tobinai, K., Miyazaki, Y., Takaori-Kondo, A., Matsuda, F., Takeuchi, K., Nureki, O., Aburatani, H., Watanabe, T., Shibata, T., Matsuoka, M., Miyano, S., Shimoda, K. and Ogawa, S.

Nat Genet 47 ( 11 ) 1304 - 15 2015.11

ISSN 1546-1718

Adult T cell leukemia/lymphoma (ATL) is a peripheral T cell neoplasm of largely unknown genetic basis, associated with human T cell leukemia virus type-1 (HTLV-1) infection. Here we describe an integrated molecular study in which we performed whole-genome, exome, transcriptome and targeted resequencing, as well as array-based copy number and methylation analyses, in a total of 426 ATL cases. The identified alterations overlap significantly with the HTLV-1 Tax interactome and are highly enriched for T cell receptor-NF-kappaB signaling, T cell trafficking and other T cell-related pathways as well as immunosurveillance. Other notable features include a predominance of activating mutations (in PLCG1, PRKCB, CARD11, VAV1, IRF4, FYN, CCR4 and CCR7) and gene fusions (CTLA4-CD28 and ICOS-CD28). We also discovered frequent intragenic deletions involving IKZF2, CARD11 and TP73 and mutations in GATA3, HNRNPA2B1, GPR183, CSNK2A1, CSNK2B and CSNK1A1. Our findings not only provide unique insights into key molecules in T cell signaling but will also guide the development of new diagnostics and therapeutics in this intractable tumor.

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Targeted gene correction of RUNX1 in induced pluripotent stem cells derived from familial platelet disorder with propensity to myeloid malignancy restores normal megakaryopoiesis

Iizuka, H., Kagoya, Y., Kataoka, K., Yoshimi, A., Miyauchi, M., Taoka, K., Kumano, K., Yamamoto, T., Hotta, A., Arai, S. and Kurokawa, M.

Exp Hematol 43 ( 10 ) 849 - 57 2015.10

ISSN 1873-2399

Familial platelet disorder with propensity to acute myeloid leukemia (FPD/AML) is an autosomal dominant disease associated with a germline mutation in the RUNX1 gene and is characterized by thrombocytopenia and an increased risk of developing myeloid malignancies. We generated induced pluripotent stem cells (iPSCs) from dermal fibroblasts of a patient with FPD/AML possessing a nonsense mutation R174X in the RUNX1 gene. Consistent with the clinical characteristics of the disease, FPD iPSC-derived hematopoietic progenitor cells were significantly impaired in undergoing megakaryocytic differentiation and subsequent maturation, as determined by colony-forming cell assay and surface marker analysis. Notably, when we corrected the RUNX1 mutation using transcription activator-like effector nucleases in conjunction with a donor plasmid containing normal RUNX1 cDNA sequences, megakaryopoiesis and subsequent maturation were restored in FPD iPSC-derived hematopoietic cells. These findings clearly indicate that the RUNX1 mutation is robustly associated with thrombocytopenia in patients with FPD/AML, and transcription activator-like effector nuclease-mediated gene correction in iPSCs generated from patient-derived cells could provide a promising clinical application for treatment of the disease.

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Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia

Yoshizato, T., Dumitriu, B., Hosokawa, K., Makishima, H., Yoshida, K., Townsley, D., Sato-Otsubo, A., Sato, Y., Liu, D., Suzuki, H., Wu, C. O., Shiraishi, Y., Clemente, M. J., Kataoka, K., Shiozawa, Y., Okuno, Y., Chiba, K., Tanaka, H., Nagata, Y., Katagiri, T., Kon, A., Sanada, M., Scheinberg, P., Miyano, S., Maciejewski, J. P., Nakao, S., Young, N. S. and Ogawa, S.

N Engl J Med 373 ( 1 ) 35 - 47 2015.07

ISSN 1533-4406

BACKGROUND: In patients with acquired aplastic anemia, destruction of hematopoietic cells by the immune system leads to pancytopenia. Patients have a response to immunosuppressive therapy, but myelodysplastic syndromes and acute myeloid leukemia develop in about 15% of the patients, usually many months to years after the diagnosis of aplastic anemia. METHODS: We performed next-generation sequencing and array-based karyotyping using 668 blood samples obtained from 439 patients with aplastic anemia. We analyzed serial samples obtained from 82 patients. RESULTS: Somatic mutations in myeloid cancer candidate genes were present in one third of the patients, in a limited number of genes and at low initial variant allele frequency. Clonal hematopoiesis was detected in 47% of the patients, most frequently as acquired mutations. The prevalence of the mutations increased with age, and mutations had an age-related signature. DNMT3A-mutated and ASXL1-mutated clones tended to increase in size over time; the size of BCOR- and BCORL1-mutated and PIGA-mutated clones decreased or remained stable. Mutations in PIGA and BCOR and BCORL1 correlated with a better response to immunosuppressive therapy and longer and a higher rate of overall and progression-free survival; mutations in a subgroup of genes that included DNMT3A and ASXL1 were associated with worse outcomes. However, clonal dynamics were highly variable and might not necessarily have predicted the response to therapy and long-term survival among individual patients. CONCLUSIONS: Clonal hematopoiesis was prevalent in aplastic anemia. Some mutations were related to clinical outcomes. A highly biased set of mutations is evidence of Darwinian selection in the failed bone marrow environment. The pattern of somatic clones in individual patients over time was variable and frequently unpredictable. (Funded by Grant-in-Aid for Scientific Research and others.).

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Mutational landscape and clonal architecture in grade II and III gliomas

Suzuki, H., Aoki, K., Chiba, K., Sato, Y., Shiozawa, Y., Shiraishi, Y., Shimamura, T., Niida, A., Motomura, K., Ohka, F., Yamamoto, T., Tanahashi, K., Ranjit, M., Wakabayashi, T., Yoshizato, T., Kataoka, K., Yoshida, K., Nagata, Y., Sato-Otsubo, A., Tanaka, H., Sanada, M., Kondo, Y., Nakamura, H., Mizoguchi, M., Abe, T., Muragaki, Y., Watanabe, R., Ito, I., Miyano, S., Natsume, A. and Ogawa, S.

Nat Genet 47 ( 5 ) 458 - 68 2015.05

ISSN 1546-1718

Grade II and III gliomas are generally slowly progressing brain cancers, many of which eventually transform into more aggressive tumors. Despite recent findings of frequent mutations in IDH1 and other genes, knowledge about their pathogenesis is still incomplete. Here, combining two large sets of high-throughput sequencing data, we delineate the entire picture of genetic alterations and affected pathways in these glioma types, with sensitive detection of driver genes. Grade II and III gliomas comprise three distinct subtypes characterized by discrete sets of mutations and distinct clinical behaviors. Mutations showed significant positive and negative correlations and a chronological hierarchy, as inferred from different allelic burdens among coexisting mutations, suggesting that there is functional interplay between the mutations that drive clonal selection. Extensive serial and multi-regional sampling analyses further supported this finding and also identified a high degree of temporal and spatial heterogeneity generated during tumor expansion and relapse, which is likely shaped by the complex but ordered processes of multiple clonal selection and evolutionary events.

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Evi1 defines leukemia-initiating capacity and tyrosine kinase inhibitor resistance in chronic myeloid leukemia

Sato, T., Goyama, S., Kataoka, K., Nasu, R., Tsuruta-Kishino, T., Kagoya, Y., Nukina, A., Kumagai, K., Kubota, N., Nakagawa, M., Arai, S., Yoshimi, A., Honda, H., Kadowaki, T. and Kurokawa, M.

Oncogene 33 ( 42 ) 5028 - 38 2014.10

ISSN 1476-5594

Relapse of chronic myeloid leukemia (CML) is triggered by stem cells with a reconstituting capacity similar to that of hematopoietic stem cells (HSCs) and CML stem cells are a source of resistance in drug therapy with tyrosine kinase inhibitors (TKIs). Ecotropic viral integration site 1 (EVI1), a key transcription factor in HSC regulation, is known to predict poor outcomes in myeloid malignancies, however, incapability of prospective isolation of EVI1-high leukemic cells precludes the functional evaluation of intraindividual EVI1-high cells. Introduction of CML into Evi1-internal ribosomal entry site (IRES)-green fluorescent protein (GFP) knock-in mice, a versatile HSC-reporter strain, enables us to separate Evi1-high CML cells from the individual. Evi1-IRES-GFP allele models of CML in chronic phase (CML-CP), by retroviral overexpression of BCR-ABL and by crossing BCR-ABL transgenic mice, revealed that Evi1 is predominantly enriched in the stem cell fraction and associated with an enhanced proliferative as well as a leukemia-initiating capacity and that Evi1-high CML-CP cells exhibit resistance to TKIs. Overexpressing BCR-ABL and NUP98-HOXA9 in Evi1-IRES-GFP knock-in mice to model CML in blast crisis (CML-BC), in which Evi1-high cells turned to be a major population as opposed to a minor population in CML-CP models, showed that Evi1-high CML-BC cells have a greater potential to recapitulate the disease and appear resistant to TKIs. Furthermore, given that Evi1 heterozygosity ameliorates CML-CP and CML-BC development and that the combination of Evi1 and BCR-ABL causes acute myeloid leukemia resembling CML-BC, Evi1 could regulate CML development as a potent driver. In addition, in human CML-CP cases, we show that EVI1 is highly expressed in stem cell-enriched CD34+CD38-CD90+ fraction at single-cell level. This is the first report to clarify directly that Evi1-high leukemic cells themselves possess the superior potential to Evi1-low cells in oncogenic self-renewal, which highlights the role of Evi1 as a valuable and a functional marker of CML stem cells.

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Generation of induced pluripotent stem cells derived from primary and secondary myelofibrosis patient samples

Hosoi, M., Kumano, K., Taoka, K., Arai, S., Kataoka, K., Ueda, K., Kamikubo, Y., Takayama, N., Otsu, M., Eto, K., Nakauchi, H. and Kurokawa, M.

Exp Hematol 42 ( 9 ) 816 - 25 2014.09

ISSN 1873-2399

Induced pluripotent stem cells (iPS) derived from disease cells are expected to provide a new experimental material, especially for diseases from which samples are difficult to obtain. In this study, we generated iPS from samples from patients with primary and secondary myelofibrosis. The primary myelofibrosis cells had chromosome 13q deletions, and the secondary myelofibrosis (SMF) cells had JAK2V617F mutations. The myelofibrosis patient cell-derived iPS (MF-iPS) were confirmed as possessing these parental disease-specific genomic markers. The capacity to form three germ layers was confirmed by teratoma assay. By co-culture with specific feeder cells and cytokines, MF-iPS can re-differentiate into blood progenitor cells and finally into megakaryocytes. We found that mRNA levels of interleukin-8, one of the candidate cytokines related to the pathogenesis of myelofibrosis, was elevated predominantly in megakaryocytes derived from MF-iPS. Because megakaryocytes from myelofibrosis clones are considered to produce critical mediators to proliferate fibroblasts in the bone marrow and iPS can provide differentiated cells abundantly, the disease-specific iPS we established should be a good research tool for this intractable disease.

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Recurrent somatic mutations underlie corticotropin-independent Cushing's syndrome

Sato, Y., Maekawa, S., Ishii, R., Sanada, M., Morikawa, T., Shiraishi, Y., Yoshida, K., Nagata, Y., Sato-Otsubo, A., Yoshizato, T., Suzuki, H., Shiozawa, Y., Kataoka, K., Kon, A., Aoki, K., Chiba, K., Tanaka, H., Kume, H., Miyano, S., Fukayama, M., Nureki, O., Homma, Y. and Ogawa, S.

Science 344 ( 6186 ) 917 - 20 2014.05

ISSN 1095-9203

Cushing's syndrome is caused by excess cortisol production from the adrenocortical gland. In corticotropin-independent Cushing's syndrome, the excess cortisol production is primarily attributed to an adrenocortical adenoma, in which the underlying molecular pathogenesis has been poorly understood. We report a hotspot mutation (L206R) in PRKACA, which encodes the catalytic subunit of cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), in more than 50% of cases with adrenocortical adenomas associated with corticotropin-independent Cushing's syndrome. The L206R PRKACA mutant abolished its binding to the regulatory subunit of PKA (PRKAR1A) that inhibits catalytic activity of PRKACA, leading to constitutive, cAMP-independent PKA activation. These results highlight the major role of cAMP-independent activation of cAMP/PKA signaling by somatic mutations in corticotropin-independent Cushing's syndrome, providing insights into the diagnosis and therapeutics of this syndrome.

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The IL-2/CD25 axis maintains distinct subsets of chronic myeloid leukemia-initiating cells

Kobayashi, C. I., Takubo, K., Kobayashi, H., Nakamura-Ishizu, A., Honda, H., Kataoka, K., Kumano, K., Akiyama, H., Sudo, T., Kurokawa, M. and Suda, T.

Blood 123 ( 16 ) 2540 - 9 2014.04

ISSN 1528-0020

Just as normal stem cells require niche cells for survival, leukemia-initiating cells (LICs) may also require niche cells for their maintenance. Chronic myeloid leukemia (CML) is caused by the activity of BCR-ABL, a constitutively active tyrosine kinase. CML therapy with tyrosine kinase inhibitors is highly effective; however, due to the persistence of residual LICs, it is not curative. Several factors are known to support CML LICs, but purification of LICs and a thorough understanding of their niche signals have not yet been achieved. Using a CML-like mouse model of myeloproliferative disease, we demonstrate that CML LICs can be divided into CD25(+)FcepsilonRIalpha(-) Lineage marker (Lin)(-) Sca-1(+)c-Kit(+) (F(-)LSK) cells and CD25(-)F(-)LSK cells. The CD25(+)F(-)LSK cells had multilineage differentiation capacity, with a preference toward cytokine-producing mast cell commitment. Although cells interconverted between CD25(-)F(-)LSK and CD25(+)F(-)LSK status, the CD25(+)F(-)LSK cells exhibited higher LIC capacity. Our findings suggest that interleukin-2 derived from the microenvironment and CD25 expressed on CML LICs constitute a novel signaling axis. The high levels of CD25 expression in the CD34(+)CD38(-) fraction of human CML cells indicate that CD25(+) LICs constitute an "LIC-derived niche" that could be preferentially targeted in therapy for CML.

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Positive feedback between NF-kappaB and TNF-alpha promotes leukemia-initiating cell capacity

Kagoya, Y., Yoshimi, A., Kataoka, K., Nakagawa, M., Kumano, K., Arai, S., Kobayashi, H., Saito, T., Iwakura, Y. and Kurokawa, M.

J Clin Invest 124 ( 2 ) 528 - 42 2014.02

ISSN 1558-8238

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy that originates from leukemia-initiating cells (LICs). The identification of common mechanisms underlying LIC development will be important in establishing broadly effective therapeutics for AML. Constitutive NF-kappaB pathway activation has been reported in different types of AML; however, the mechanism of NF-kappaB activation and its importance in leukemia progression are poorly understood. Here, we analyzed myeloid leukemia mouse models to assess NF-kappaB activity in AML LICs. We found that LICs, but not normal hematopoietic stem cells or non-LIC fractions within leukemia cells, exhibited constitutive NF-kappaB activity. This activity was maintained through autocrine TNF-alpha secretion, which formed an NF-kappaB/TNF-alpha positive feedback loop. LICs had increased levels of active proteasome machinery, which promoted the degradation of IkappaBalpha and further supported NF-kappaB activity. Pharmacological inhibition of the proteasome complex markedly suppressed leukemia progression in vivo. Conversely, enhanced activation of NF-kappaB signaling expanded LIC frequency within leukemia cell populations. We also demonstrated a strong correlation between NF-kappaB activity and TNF-alpha secretion in human AML samples. Our findings indicate that NF-kappaB/TNF-alpha signaling in LICs contributes to leukemia progression and provide a widely applicable approach for targeting LICs.

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Identification of long-term repopulating hematopoietic stem cells by Evi1

Kataoka, Keisuke, Sato, Tomohiko and Kurokawa, Mineo

Inflammation and Regeneration 33 ( 4 ) 175 - 180 2013

ISSN 1880-9693

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