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Dive into the research topics where Makoto Yoshimitsu is active.

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Featured researches published by Makoto Yoshimitsu.


International Journal of Cancer | 2012

High expression of the longevity gene product SIRT1 and apoptosis induction by sirtinol in adult T-cell leukemia cells

Tomohiro Kozako; Akiyoshi Aikawa; Teruhisa Shoji; Takahiro Fujimoto; Makoto Yoshimitsu; Senji Shirasawa; Shin-ichiro Honda; Hiroshi Shimeno; Naomichi Arima; Shinji Soeda

Adult T‐cell leukemia‐lymphoma (ATL) is an aggressive peripheral T‐cell neoplasm that develops after long‐term infection with human T‐cell leukemia virus (HTLV‐1). SIRT1, a nicotinamide adenine dinucleotide+‐dependent histone/protein deacetylase, plays a crucial role in various physiological processes, such as aging, metabolism, neurogenesis and apoptosis, owing to its ability to deacetylate numerous substrates, such as histone and NF‐κB, which is implicated as an exacerbation factor in ATL. Here, we assessed how SIRT1 is regulated in primary ATL cells and leukemic cell lines. SIRT1 expression in ATL patients was significantly higher than that in healthy controls, especially in the acute type. Sirtinol, a SIRT1 inhibitor, induced significant growth inhibition or apoptosis in cells from ATL patients and leukemic cell lines, especially HTLV‐1‐related cell lines. Sirtinol‐induced apoptosis was mediated by activation of the caspase family and degradation of SIRT1 in the nucleus. Furthermore, SIRT1 knockdown by SIRT1‐specific small interfering RNA caused apoptosis via activation of caspase‐3 and PARP in MT‐2 cells, HTLV‐1‐related cell line. These results suggest that SIRT1 is a crucial antiapoptotic molecule in ATL cells and that SIRT1 inhibitors may be useful therapeutic agents for leukemia, especially in patients with ATL.


Blood | 2015

Loss-of-TET2 has dual roles in murine myeloproliferative neoplasms: disease sustainer and disease accelerator

Takuro Kameda; Kotaro Shide; Takumi Yamaji; Ayako Kamiunten; Masaaki Sekine; Yasuhiro Taniguchi; Tomonori Hidaka; Yoko Kubuki; Haruko Shimoda; Kousuke Marutsuka; Goro Sashida; Kazumasa Aoyama; Makoto Yoshimitsu; Taku Harada; Hiroo Abe; Tadashi Miike; Hisayoshi Iwakiri; Yoshihiro Tahara; Mitsue Sueta; S. Yamamoto; Satoru Hasuike; Kenji Nagata; Atsushi Iwama; Akira Kitanaka; Kazuya Shimoda

Acquired mutations of JAK2 and TET2 are frequent in myeloproliferative neoplasms (MPNs). We examined the individual and cooperative effects of these mutations on MPN development. Recipients of JAK2V617F cells developed primary myelofibrosis-like features; the addition of loss of TET2 worsened this JAK2V617F-induced disease, causing prolonged leukocytosis, splenomegaly, extramedullary hematopoiesis, and modestly shorter survival. Double-mutant (JAK2V617F plus loss of TET2) myeloid cells were more likely to be in a proliferative state than JAK2V617F single-mutant myeloid cells. In a serial competitive transplantation assay, JAK2V617F cells resulted in decreased chimerism in the second recipients, which did not develop MPNs. In marked contrast, cooperation between JAK2V617F and loss of TET2 developed and maintained MPNs in the second recipients by compensating for impaired hematopoietic stem cell (HSC) functioning. In-vitro sequential colony formation assays also supported the observation that JAK2V617F did not maintain HSC functioning over the long-term, but concurrent loss of TET2 mutation restored it. Transcriptional profiling revealed that loss of TET2 affected the expression of many HSC signature genes. We conclude that loss of TET2 has two different roles in MPNs: disease accelerator and disease initiator and sustainer in combination with JAK2V617F.


Gene Therapy | 2007

Efficient correction of Fabry mice and patient cells mediated by lentiviral transduction of hematopoietic stem/progenitor cells.

Makoto Yoshimitsu; Koji Higuchi; Shobha Ramsubir; Takahiro Nonaka; Vanessa I. Rasaiah; Christopher Siatskas; Sheng-Ben Liang; Gary J. Murray; Roscoe O. Brady; Jeffrey A. Medin

A deficiency in α-galactosidase A (α-gal A) activity causes Fabry disease. Virus-based delivery of genes can correct cells and establish a sustained supply of therapeutic proteins. Recombinant lentiviral vectors (LVs) show promise in this context. We first demonstrate LV-mediated marking of peripheral blood (PB) cells by transduction/transplantation of hematopoietic stem/progenitor cells. Stable enGFP expression was observed in PB for 37 weeks. Next, we transplanted Fabry mice with bone marrow mononuclear cells (BMMNCs) transduced a single time with a LV encoding the human α-gal A cDNA. Sustained expression of functional α-gal A in Fabry mice was observed over 24 weeks. Plasma α-gal A activity from treated Fabry mice was two-fold higher than wild-type controls. Increased α-gal A activity, often to supra-normal levels, and reduction of globotriaosylceramide, a glycolipid that accumulates in Fabry disease, was observed in all organs assessed. In secondary bone marrow transplantations, Fabry mice showed multilineage marking of PB, splenocytes and BMMNCs, along with therapeutic levels of α-gal A activity in plasma and organs over 20 weeks. Lastly, we transduced mobilized PB CD34+ cells from a Fabry patient and observed corresponding enzymatic increases. Thus a single LV-mediated transduction of primitive hematopoietic cells can result in sustained correction for Fabry disease.


Human Cell | 2012

Establishment of a highly migratory subclone reveals that CD133 contributes to migration and invasion through epithelial–mesenchymal transition in pancreatic cancer

Qiang Ding; Makoto Yoshimitsu; Taisaku Kuwahata; Koki Maeda; Tomomi Hayashi; Toru Obara; Yumi Miyazaki; Shyuichiro Matsubara; Shoji Natsugoe; Sonshin Takao

Pancreatic cancer is a lethal disease because of invasion and early metastasis. Although CD133, a marker of cancer stem cells (CSCs) in a variety of solid tumors, has been studied in recent decades, its function remains obscure. Recent reports suggest that epithelial–mesenchymal transition (EMT) may be related to the properties of CSCs. In this study, we investigated whether CSC markers are associated with EMT. For Capan1M9, a highly migratory cell subclone established from human pancreatic cancer cell line Capan-1, CD133 expression, migration, and invasion were greater than for the parent cells. In Capan1M9 cells, the EMT-related transcription factors Slug and Snail were up-regulated, and N-cadherin and fibronectin were also substantially increased. In contrast, occludin and desmoplakin were suppressed. Knockdown of endogenous CD133 in the Capan1M9 cells led to Slug suppression and reduction of migration and invasion. Taken together, CD133 has an important role in migration and invasion by facilitating EMT in pancreatic cancer cells.


Pathology International | 2014

Two autopsy cases of severe fever with thrombocytopenia syndrome (SFTS) in Japan: A pathognomonic histological feature and unique complication of SFTS

Tsubasa Hiraki; Makoto Yoshimitsu; Tadaki Suzuki; Yuko Goto; Michiyo Higashi; Seiya Yokoyama; Tomohisa Tabuchi; Takahiro Futatsuki; Kentaro Nakamura; Hideki Hasegawa; Masayuki Saijo; Yasuyuki Kakihana; Naomichi Arima; Suguru Yonezawa

We report two autopsy cases of severe fever with thrombocytopenia syndrome (SFTS) with a high fatality rate in aged Japanese patients. Both cases were caused by a tick‐bite. The pathognomonic histological feature was necrotizing lymphadenitis of systemic lymphoid tissue with SFTS viruses and SFTSV‐RNA copies. Marked fungal infections were also observed in the lungs of both patients. Since cellular immune function may be suppressed in SFTS patients, physicians should be aware of possible fungal infections.


Journal of Clinical Oncology | 2016

Multicenter Phase II Study of Lenalidomide in Relapsed or Recurrent Adult T-Cell Leukemia/Lymphoma: ATLL-002.

Takashi Ishida; Hiroshi Fujiwara; Kisato Nosaka; Naoya Taira; Yasunobu Abe; Yoshitaka Imaizumi; Yukiyoshi Moriuchi; Tatsuro Jo; Kenichi Ishizawa; Kensei Tobinai; Kunihiro Tsukasaki; Shigeki Ito; Makoto Yoshimitsu; Maki Otsuka; Michinori Ogura; Shuichi Midorikawa; Wanda Ruiz; Tomoko Ohtsu

Purpose Few treatment options exist for adult T-cell leukemia/lymphoma (ATL), and the prognosis for this disease is poor. A phase I study of lenalidomide demonstrated preliminary antitumor activity in patients with relapsed ATL. The current phase II study evaluated the efficacy and safety of lenalidomide monotherapy in patients with relapsed or recurrent ATL. Patients and Methods Patients 20 years of age or older with acute, lymphoma, or unfavorable chronic subtype ATL, who had received one or more prior anti-ATL systemic chemotherapy and achieved stable disease or better on their last anti-ATL therapy with subsequent relapse or recurrence, were eligible. Patients received oral lenalidomide 25 mg/d continuously until disease progression or unacceptable toxicity. The primary end point was overall response rate; secondary end points included safety, tumor control rate (stable disease or better), time to response, duration of response, time to progression, progression-free survival, and overall survival. Results Objective responses were noted in 11 of 26 patients (overall response rate, 42%; 95% CI, 23% to 63%), including four complete responses and one unconfirmed complete response. The tumor control rate was 73%. The median time to response and duration of response were 1.9 months and not estimable, respectively, and the median time to progression was 3.8 months. The median progression-free survival and overall survival were 3.8 and 20.3 months, respectively. The most frequent grade ≥ 3 adverse events were neutropenia (65%), leukopenia (38%), lymphopenia (38%), and thrombocytopenia (23%), which were all manageable and reversible. Conclusion Lenalidomide demonstrated clinically meaningful antitumor activity and an acceptable toxicity profile in patients with relapsed or recurrent aggressive ATL, hinting at its potential to become a treatment option. Further investigations of lenalidomide in ATL and other mature T-cell neoplasms are warranted.


Molecules | 2014

Anticancer Agents Targeted to Sirtuins

Tomohiro Kozako; Takayoshi Suzuki; Makoto Yoshimitsu; Naomichi Arima; Shin-ichiro Honda; Shinji Soeda

Sirtuins are nicotinamide adenine dinucleotide+-dependent deacetylases of which there are seven isoforms (SIRT1–7). Sirtuin activity is linked to gene expression, lifespan extension, neurodegeneration, and age-related disorders. Numerous studies have suggested that sirtuins could be of great significance with regard to both antiaging and tumorigenesis, depending on its targets in specific signaling pathways or in specific cancers. Recent studies have identified small chemical compounds that modulate sirtuins, and these modulators have enabled a greater understanding of the biological function and molecular mechanisms of sirtuins. This review highlights the possibility of sirtuins, especially SIRT1 and SIRT2, for cancer therapy targets, and focuses on the therapeutic potential of sirtuin modulators both in cancer prevention and treatment.


Molecular Cancer | 2014

CD133 facilitates epithelial-mesenchymal transition through interaction with the ERK pathway in pancreatic cancer metastasis

Qiang Ding; Yumi Miyazaki; Koichiro Tsukasa; Shyuichiro Matsubara; Makoto Yoshimitsu; Sonshin Takao

BackgroundPancreatic cancer is a lethal disease due to the high incidence of metastasis at the time of detection. CD133 expression in clinical pancreatic cancer correlates with poor prognosis and metastasis. However, the molecular mechanism of CD133-regulated metastasis remains unclear. In recent years, epithelial-mesenchymal transition (EMT) has been linked to cancer invasion and metastasis. In the present study we investigated the role of CD133 in pancreatic cancer metastasis and its potential regulatory network.MethodsA highly migratory pancreatic cancer cell line, Capan1M9, was established previously. After shRNA was stable transducted to knock down CD133 in Capan1M9 cells, gene expression was profiled by DNA microarray. Orthotopic, splenic and intravenous transplantation mouse models were set up to examine the tumorigenesis and metastatic capabilities of these cells. In further experiments, real-time RT-PCR, Western blot and co-immunoprecipitate were conducted to evaluate the interactions of CD133, Slug, N-cadherin, ERK1/2 and SRC.ResultsWe found that CD133+ human pancreatic cancer cells were prone to generating metastatic nodules in in vivo models using immunodeficient mice. In contrast, CD133 knockdown suppressed cancer invasion and metastasis in vivo. Gene profiling analysis suggested that CD133 modulated mesenchymal characteristics including the expression of EMT-related genes, such as Slug and N-cadherin. These genes were down-regulated following CD133 knockdown. Moreover, CD133 expression could be modulated by the extracellular signal-regulated kinase (ERK)1/2 and SRC signaling pathways. The binding of CD133 to ERK1/2 and SRC acts as an indispensable mediator of N-cadherin expression.ConclusionsThese results demonstrate that CD133 plays a critical role in facilitating the EMT regulatory loop, specifically by upregulating N-cadherin expression, leading to the invasion and metastasis of pancreatic cancer cells. Our study provides a novel insight into the function of CD133 in the EMT program and a better understanding of the mechanism underlying the involvement of CD133 in pancreatic cancer metastasis.


Biology of Blood and Marrow Transplantation | 2015

A Retrospective Analysis of Treatment Outcomes in Adult T Cell Leukemia/Lymphoma Patients with Aggressive Disease Treated with or without Allogeneic Stem Cell Transplantation: A Single-Center Experience

Hideaki Kawada; Makoto Yoshimitsu; Daisuke Nakamura; Akihiko Arai; Maiko Hayashida; Yuhei Kamada; Kenichi Maekawa; Satoshi Fujino; Mamiko Arima; Naosuke Arima; Tomohisa Tabuchi; Hirosaka Inoue; Heiichiro Hamda; Shinsuke Suzuki; Kakushi Matsushita; Naomichi Arima

Adult T cell leukemia/lymphoma (ATL) is an aggressive peripheral T cell neoplasm with very poor prognosis. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been reported as a curative treatment modality for ATL. However, there are no reports comparing chemotherapy alone with allo-HSCT in ATL. In this report, we retrospectively analyzed data for patients treated with (n = 29, median age 55 years) or without allo-HSCT (n = 37, median age 58 years) for ATL in Kagoshima University Hospital, located in one of the most endemic areas of human T cell lymphotropic leukemia virus type 1 infection. Forty patients (61%) started coordination for allo-HSCT. Ten patients (34.4%) received allo-HSCT while in complete remission (CR), whereas the others were not in CR. Twenty-five patients (86.2%) received reduced-intensity conditioning, and the others received myeloablative conditioning. With a median follow-up period for survivors of 41 months (range, 5 to 125 months), the 3-year overall survival (OS) rate from first chemotherapy for all patients (with or without allo-HSCT) was 35.2%. The 3-year OS from first chemotherapy for patients who received allo-HSCT or only chemotherapy was 44.9% and 27.7%, respectively. Univariate analyses revealed that high serum soluble IL-2 receptor (sIL-2R) levels (≥ 2000 U/mL) just before the conditioning regimen and progressive disease (PD) status at HSCT (according to Japan Clinical Oncology Group Study 0907 criteria) were significant risk factors for OS in the allo-HSCT group. Multivariate analyses revealed that PD status was a significant risk factor for OS in the allo-HSCT group. In the chemotherapy-only group, the 3-year OS rate was 61.5% (95% CI, 30.8% to 81.8%) in patients with serum sIL-2R levels < 2000 U/mL for > 3 months. In contrast, the 3-year OS rate was 5.7% (95% CI, .4% to 22.4%) in patients who did not achieve serum sIL-2R levels < 2000 U/mL for >3 months. Our single-center cohort experience indicates that chemosensitivity is the most important prognostic factor for OS in ATL patients and the use of allo-HSCT is limited in chemorefractory patients with aggressive ATL disease. In the chemosensitive patients, allo-HSCT demonstrated a tendency toward better OS. Further clinical studies are warranted to determine optimal treatments for patients who are less sensitive to conventional chemotherapy.


FEBS Journal | 2011

Oligomannose‐coated liposomes efficiently induce human T‐cell leukemia virus‐1‐specific cytotoxic T lymphocytes without adjuvant

Tomohiro Kozako; Shinya Hirata; Yoshitaka Shimizu; Yuichiro Satoh; Makoto Yoshimitsu; Yohann White; François A. Lemonnier; Hiroshi Shimeno; Shinji Soeda; Naomichi Arima

Human T‐cell leukemia virus‐1 (HTLV‐1) causes adult T‐cell leukemia/lymphoma, which is an aggressive peripheral T‐cell neoplasm. Insufficient T‐cell response to HTLV‐1 is a potential risk factor in adult T‐cell leukemia/lymphoma. Efficient induction of antigen‐specific cytotoxic T lymphocytes is important for immunological suppression of virus‐infected cell proliferation and oncogenesis, but efficient induction of antigen‐specific cytotoxic T lymphocytes has evaded strategies utilizing poorly immunogenic free synthetic peptides. Here, we examined the efficient induction of an HTLV‐1‐specific CD8+ T‐cell response by oligomannose‐coated liposomes (OMLs) encapsulating the human leukocyte antigen (HLA)‐A*0201‐restricted HTLV‐1 Tax‐epitope (OML/Tax). Immunization of HLA‐A*0201 transgenic mice with OML/Tax induced an HTLV‐1‐specific gamma‐interferon reaction, whereas immunization with epitope peptide alone induced no reaction. Upon exposure of dendritic cells to OML/Tax, the levels of CD86, major histocompatibility complex class I, HLA‐A02 and major histocompatibility complex class II expression were increased. In addition, our results showed that HTLV‐1‐specific CD8+ T cells can be efficiently induced by OML/Tax from HTLV‐1 carriers compared with epitope peptide alone, and these HTLV‐1‐specific CD8+ T cells were able to lyse cells presenting the peptide. These results suggest that OML/Tax is capable of inducing antigen‐specific cellular immune responses without adjuvants and may be useful as an effective vaccine carrier for prophylaxis in tumors and infectious diseases by substituting the epitope peptide.

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Jeffrey A. Medin

Medical College of Wisconsin

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Koji Higuchi

University Health Network

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