論文 - 籠谷　勇紀

Thrombopoietin/MPL signaling confers growth and survival capacity to CD41-positive cells in a mouse model of Evi1 leukemia

Satoshi Nishikawa, Shunya Arai, Yosuke Masamoto, Yuki Kagoya, Takashi Toya, Naoko Watanabe-Okochi, Mineo Kurokawa

Blood （American Society of Hematology）  124 （ 24 ） 3587 - 3596 2014年12月

査読有り,  ISSN  0006-4971

　概要を見る

AML1-ETO (AE) is a fusion product of translocation (8;21) that accounts for 40% of M2 type acute myeloid leukemia (AML). In addition to its role in promoting preleukemic hematopoietic cell self-renewal, AE represses DNA repair genes, which leads to DNA damage and increased mutation frequency. Although this latter function may promote leukemogenesis, concurrent p53 activation also leads to an increased baseline apoptotic rate. It is unclear how AE expression is able to counterbalance this intrinsic apoptotic conditioning by p53 to promote survival and self-renewal. In this report, we show that Bcl-xL is up-regulated in AE cells and plays an essential role in their survival and self-renewal. Further investigation revealed that Bcl-xL expression is regulated by thrombopoietin (THPO)/MPL-signaling induced by AE expression. THPO/MPL-signaling also controls cell cycle reentry and mediates AE-induced self-renewal. Analysis of primary AML patient samples revealed a correlation between MPL and Bcl-xL expression specifically in t(8;21) blasts. Taken together, we propose that survival signaling through Bcl-xL is a critical and intrinsic component of a broader self-renewal signaling pathway downstream of AML1-ETO–induced MPL.

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JAK2V617F+ myeloproliferative neoplasm clones evoke paracrine DNA damage to adjacent normal cells through secretion of lipocalin-2

Yuki Kagoya, Akihide Yoshimi, Takako Tsuruta-Kishino, Shunya Arai, Takashi Satoh, Shizuo Akira, Mineo Kurokawa

Blood （American Society of Hematology）  124 （ 19 ） 2996 - 3006 2014年11月

筆頭著者, 査読有り,  ISSN  0006-4971

　概要を見る

Genetic instability is strongly involved in cancer development and progression, and elucidating the mechanism could lead to novel therapeutics for preventing carcinogenesis. Philadelphia-negative myeloproliferative neoplasms (MPNs) are clonal myeloid disorders with a high prevalence of JAK2V617F mutation, and transformation to acute myeloid leukemia through accumulation of additional mutations is a major complication in MPNs. Here, we showed that JAK2V617F+ cells conferred paracrine DNA damage to neighboring normal cells as well as to themselves through increased reactive oxygen species (ROS). We screened candidate factors responsible for the effect and found that lipocalin-2 (Lcn2) is overexpressed in JAK2V617F+ cells and that short hairpin RNA–mediated knockdown of Lcn2 significantly alleviated the paracrine DNA damage. Normal hematopoietic cells showed elevated ROS levels through increased intracellular iron levels when treated with lipocalin-2, which led to p53 pathway activation, increased apoptosis, and decreased cellular proliferation. In contrast, JAK2V617F+ cells did not suffer from lipocalin-2–induced growth suppression resulting from attenuated p53 pathway activation, which conferred a relative growth advantage to JAK2V617F+ clones. In summary, we demonstrated that JAK2V617F-harboring cells cause paracrine DNA damage accumulation through secretion of lipocalin-2, which gives proliferative advantage to themselves and an increased risk for leukemic transformation to both JAK2V617F+ and JAK2V617F– clones.

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

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

Oncogene （Springer Science and Business Media LLC）  33 （ 42 ） 5028 - 5038 2014年10月

査読有り,  ISSN  0950-9232

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Gene expression profiles of central nervous system lymphoma predict poor survival in patients with diffuse large B-cell lymphoma

Yuki Kagoya, Yasuhito Nannya, Fumihiko Nakamura, Mineo Kurokawa

British Journal of Haematology （Wiley）  166 （ 5 ） 794 - 797 2014年09月

筆頭著者, 査読有り,  ISSN  0007-1048

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Inhibition of histone methyltransferase EZH 2 depletes leukemia stem cell of mixed lineage leukemia fusion leukemia through upregulation of p16

Koki Ueda, Akihide Yoshimi, Yuki Kagoya, Satoshi Nishikawa, Victor E. Marquez, Masahiro Nakagawa, Mineo Kurokawa

Cancer Science （Wiley）  105 （ 5 ） 512 - 519 2014年05月

査読有り,  ISSN  1347-9032

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Single-cell gene expression analysis reveals clonal architecture of blast-phase chronic myeloid leukaemia

Arika Nukina, Yuki Kagoya, Naoko Watanabe-Okochi, Shunya Arai, Koki Ueda, Akihide Yoshimi, Yasuhito Nannya, Mineo Kurokawa

British Journal of Haematology （Wiley）  165 （ 3 ） 414 - 416 2014年05月

筆頭著者, 査読有り,  ISSN  0007-1048

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Positive feedback between NF-κB and TNF-α promotes leukemia-initiating cell capacity

Yuki Kagoya, Akihide Yoshimi, Keisuke Kataoka, Masahiro Nakagawa, Keiki Kumano, Shunya Arai, Hiroshi Kobayashi, Taku Saito, Yoichiro Iwakura, Mineo Kurokawa

Journal of Clinical Investigation （American Society for Clinical Investigation）  124 （ 2 ） 528 - 542 2014年02月

筆頭著者, 査読有り,  ISSN  0021-9738

　概要を見る

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-κB pathway activation has been reported in different types of AML; however, the mechanism of NF-κB activation and its importance in leukemia progression are poorly understood. Here, we analyzed myeloid leukemia mouse models to assess NF-κB activity in AML LICs. We found that LICs, but not normal hematopoietic stem cells or non-LIC fractions within leukemia cells, exhibited constitutive NF-κB activity. This activity was maintained through autocrine TNF-α secretion, which formed an NF-κB/TNF-α positive feedback loop. LICs had increased levels of active proteasome machinery, which promoted the degradation of IκBα and further supported NF-κB activity. Pharmacological inhibition of the proteasome complex markedly suppressed leukemia progression in vivo. Conversely, enhanced activation of NF-κB signaling expanded LIC frequency within leukemia cell populations. We also demonstrated a strong correlation between NF-κB activity and TNF-α secretion in human AML samples. Our findings indicate that NF-κB/TNF-α signaling in LICs contributes to leukemia progression and provide a widely applicable approach for targeting LICs.

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Thalidomide maintenance therapy for patients with multiple myeloma: Meta-analysis

Yuki Kagoya, Yasuhito Nannya, Mineo Kurokawa

Leukemia Research （Elsevier BV）  36 （ 8 ） 1016 - 1021 2012年08月

筆頭著者, 査読有り,  ISSN  0145-2126

　概要を見る

We performed a meta-analysis of randomized controlled trials comparing thalidomide maintenance with other regimens after induction chemotherapy for multiple myeloma. Overall, 6 trials including 2786 patients were identified. Patients treated with thalidomide maintenance had marginally better overall survival (hazard ratio HR 0.83, P=0.07). The improvement was especially prominent in a subgroup of studies using corticosteroids with thalidomide (HR 0.70, P=0.02). Thalidomide improved progression-free survival (HR 0.65, P<0.01), but had more frequent venous thrombosis (risk difference 0.024, P<0.05) and peripheral neuropathy (risk difference 0.072, P<0.01). These results suggest that thalidomide maintenance with corticosteroids is effective in prolonging survival for multiple myeloma.

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Hyperlipidemia after allogeneic stem cell transplantation: prevalence, risk factors, and impact on prognosis

Yuki Kagoya, Sachiko Seo, Yasuhito Nannya, Mineo Kurokawa

Clinical Transplantation （Wiley）  26 （ 2 ） E168 - E175 2012年03月

筆頭著者, 最終著者, 責任著者, 査読有り,  ISSN  0902-0063

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Hyperbilirubinemia after hematopoietic stem cell transplantation: comparison of clinical and pathologic findings in 41 autopsied cases

Yuki Kagoya, Tsuyoshi Takahashi, Yasuhito Nannya, Aya Shinozaki, Satoshi Ota, Masashi Fukayama, Mineo Kurokawa

Clinical Transplantation （Wiley）  25 （ 5 ） E552 - E557 2011年09月

筆頭著者, 査読有り,  ISSN  0902-0063

　概要を見る

Hyperbilirubinemia is often associated with morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Diagnosis of its etiology is usually made clinically among various possible causes, and analysis of histological findings as compared with the clinical diagnosis has not been performed sufficiently. We retrospectively analyzed clinical and pathological findings in 41 autopsied patients who died with hyperbilirubinemia (>2 mg/dL). Overall, liver graft-versus-host disease (GVHD) showed the most prominent discordance between clinical and pathological diagnoses. Only 11 of the 22 patients, considered to have liver GVHD clinically, had GVHD findings at autopsy. Serum gamma-glutamyl transpeptidase (GGT), GGT/aspartate aminotransferase (AST) ratio, and alkaline phosphatase (ALP)/AST ratio in GVHD patients were significantly higher compared with those without GVHD (p = 0.02, <0.01, and 0.03, respectively), which was useful in clinical diagnosis of liver GVHD. Other major findings include liver invasion of the primary malignancies in 8 patients, post-transplant lymphoproliferative disorder of the liver in two patients, and disseminated liver invasion by fungus or varicella-zoster virus in one patient, respectively. Although analysis of clinical data is useful for narrowing diagnosis, histological analysis by liver biopsy is crucially important, especially in cases suspected of having GVHD.

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Pretransplant Predictors and Posttransplant Sequels of Acute Kidney Injury after Allogeneic Stem Cell Transplantation

Yuki Kagoya, Keisuke Kataoka, Yasuhito Nannya, Mineo Kurokawa

Biology of Blood and Marrow Transplantation （Elsevier BV）  17 （ 3 ） 394 - 400 2011年03月

筆頭著者, 査読有り,  ISSN  1083-8791

　概要を見る

Acute kidney injury (AKI) is a common complication after allogeneic stem cell transplantation (SCT). Although various risk factors for AKI have been reported, the influence of pretransplant comorbidity on the incidence of AKI has not been well investigated. We performed a retrospective analysis of 207 consecutive patients undergoing myeloablative or nonmyeloablative SCT between 2001 and 2009, using the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) as a representative of pretransplant comorbidities. According to Risk, Injury, Failure, Loss, and End-stage kidney disease (RIFLE) criteria, 158 patients (76.3%) developed AKI, and 92 patients (44.4%) developed severe AKI (RIFLE class I or class F) within 100 days after SCT. The cumulative incidence of severe AKI within 100 days in patients with an HCT-CI score 0, 1-2, and ≥3 was 21.3%, 48.8%, and 73.9%, respectively. In multivariate analysis, the HCT-CI was independently associated with severe AKI (HCT-CI 1-2: adjusted hazard ratio [HR] 2.42, P < .01; HCT-CI ≥3: adjusted HR 4.69, P < .01). In a landmark analysis, patients with severe AKI had a lower 3-year overall survival (OS) (39.3% versus 61.4%, P < .01), and a higher 3-year nonrelapse mortality (NRM) (40.8% versus 5.6%, P < .01) than those without AKI. Multivariate analysis showed that severe AKI was a significant risk factor for worse OS (HR: 2.10, P = .01) and NRM (HR: 6.15, P < .01). Thus, it is important to assess the HCT-CI to predict the incidence of AKI, which is a strong indicator of worse prognosis after SCT.

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Recurrent pericardial effusion after treatment for primary effusion lymphoma-like lymphoma: an autopsied case

Yuki Kagoya, Tsuyoshi Takahashi, Toyoki Yoshimoto, Motoshi Ichikawa, Akira Hangaishi, Masashi Fukayama, Mineo Kurokawa

Annals of Hematology （Springer Science and Business Media LLC）  90 （ 2 ） 219 - 220 2011年02月

筆頭著者, 査読有り,  ISSN  0939-5555

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A Case of Primary Bone Marrow B-Cell Non Hodgkin’s Lymphoma with Severe Thrombocytopenia: Case Report and A Review of the Literature

Yuki Kagoya, Naohi Sahara, Takashi Matsunaga, Toshimasa Uekusa, Seiji Irie, Kazuhito Hatanaka

Indian Journal of Hematology and Blood Transfusion （Springer Science and Business Media LLC）  26 （ 3 ） 106 - 108 2010年09月

筆頭著者, 責任著者, 査読有り,  ISSN  0971-4502

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High-dose dexamethasone therapy for severe thrombocytopenia and neutropenia induced by EBV infectious mononucleosis

KAGOYA Yuki, HANGAISHI Akira, TAKAHASHI Tsuyoshi, IMAI Yoichi, KUROKAWA Mineo

International journal of hematology （Springer Science and Business Media LLC）  91 （ 2 ） 326 - 327 2010年03月

筆頭著者, 査読有り,  ISSN  0925-5710

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