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Featured researches published by Hidetoshi Ozawa.


Science Translational Medicine | 2010

Identification of Therapeutic Targets for Quiescent, Chemotherapy-Resistant Human Leukemia Stem Cells

Yoriko Saito; Hiroshi Kitamura; Atsushi Hijikata; Mariko Tomizawa-Murasawa; Satoshi Tanaka; Shinsuke Takagi; Naoyuki Uchida; Nahoko Suzuki; Akiko Sone; Yuho Najima; Hidetoshi Ozawa; Atsushi Wake; Shuichi Taniguchi; Leonard D. Shultz; Osamu Ohara; Fumihiko Ishikawa

CD32 and CD25, molecules specifically found in human leukemia stem cells, are promising targets for therapy. In the blood cancer acute myelogenous leukemia (AML), red blood cell precursors in the bone marrow cells divide extremely rapidly, releasing large numbers of immature cells into the bloodstream. AML can generally be treated, but many patients suffer from relapse, likely a result of pockets of residual, diseased stem cells that resist the initial treatment. To devise tools to selectively kill these cancer-initiating cells, Saito et al. have identified molecules that are unique to these cells, finding two promising surface proteins—CD32 and CD25, the alpha chain of the IL-2 receptor. To identify these markers, the authors used two microarray platforms to screen for mRNAs present in the rare leukemia stem cells but not in healthy human blood cell–generating stem cells. It was important not to choose molecules also present in normal cells to avoid potential damaging side effects by any ultimately developed therapeutic agent that targets the molecule. The two platforms yielded 217 and 75 genes, from which the authors selected genes for cell surface or extracellular proteins plus cell signaling and known regulatory proteins. They then validated the differential expression of these proteins in leukemic cells with more stringent methods, ultimately settling on 25 final candidates. In 61 samples of cells from patients with leukemia, the authors found that two of their candidate molecules, CD32 and CD25, were more frequently expressed in the leukemia stem cells than others and, in over half of the samples, there were large amounts of both of these molecules. Two additional features of CD32 and CD25 recommended these particular molecules as good targets for therapy: They remain on the leukemia stem cells, even after treatment with cytarabine, a common chemotherapy drug. And their inhibition does not interfere with normal blood cell development. The final word on the utility of these molecules as drug targets awaits further experimentation, but the stage is set for a promising test. Human acute myeloid leukemia (AML) originates from rare leukemia stem cells (LSCs). Because these chemotherapy-resistant LSCs are thought to underlie disease relapse, effective therapeutic strategies specifically targeting these cells may be beneficial. Here, we report identification of a primary human LSC gene signature and functional characterization of human LSC-specific molecules in vivo in a mouse xenotransplantation model. In 32 of 61 (53%) patients with AML, either CD32 or CD25 or both were highly expressed in LSCs. CD32- or CD25-positive LSCs could initiate AML and were cell cycle–quiescent and chemotherapy-resistant in vivo. Normal human hematopoietic stem cells depleted of CD32- and CD25-positive cells maintained long-term multilineage hematopoietic reconstitution capacity in vivo, indicating the potential safety of treatments targeting these molecules. In addition to CD32 and CD25, quiescent LSCs within the bone marrow niche also expressed the transcription factor WT1 and the kinase HCK. These molecules are also promising targets for LSC-specific therapy.


International Journal of Hematology | 2011

Activation of T-cell receptor signaling in peripheral T-cell lymphoma cells plays an important role in the development of lymphoma-associated hemophagocytosis.

Jun An; Hiroshi Fujiwara; Koichiro Suemori; Toshiyuki Niiya; Taichi Azuma; Kazushi Tanimoto; Toshiki Ochi; Yoshiki Akatsuka; Junichi Mineno; Hidetoshi Ozawa; Fumihiko Ishikawa; Kiyotaka Kuzushima; Masaki Yasukawa

Peripheral T-cell lymphoma (PTCL) is a biologically diverse lymphoid malignancy. The clinical aggressiveness associated with hemophagocytic syndrome (HS) is a characteristic of PTCL, being more distinctive in CD8+ PTCL. However, the underlying mechanism of PTCL-associated HS has not yet been fully investigated. We newly established a novel IL-2-dependent CD8+ PTCL lymphoma cell line (T8ML-1) from a patient with CD8+ PTCL who suffered recurrent HS accompanying disease flare-up. Focusing on the lymphoma cell T-cell receptor (TCR), we examined the lymphoma cell functions responsible for such clinical manifestations. First, T8ML-1.1 in which endogenous TCR-α/β chains were silenced by siRNAs, and T8ML-1.2 in which endogenous TCR-α/β chains were replaced with HLA-A*24:02-restricted and WT1235–243-specific TCR-α/β, were established. T8ML-1 exerted phytohemagglutinin (PHA)-dependent cytotoxicity via granular exocytosis. Additionally, soluble factors produced by PHA-stimulated T8ML-1, which included INF-γ and TNF-α, but not by simple-cultured T8ML-1, caused human monocytes to exhibit erythrophagocytosis and thrombophagocytosis in vitro. PHA binding induced phosphorylation of CD3ζ chain. Furthermore, both cytotoxicity and hemophagocytosis were completely inhibited by T8ML-1.1, but eventually restored by T8ML-1.2. These data suggest that exogenous activation of TCR signaling in PTCL cells might play an important role in the formation of PTCL-associated HS.


International Journal of Hematology | 2018

Notch1 expression is regulated at the post-transcriptional level by the 3′ untranslated region in hematopoietic stem cell development

Shin-ichi Mizuno; Tadafumi Iino; Hidetoshi Ozawa; Yojiro Arinobu; Yong Chong; Koichi Akashi

In hematopoiesis, the expression of critical genes is regulated in a stage-specific manner to maintain normal hematopoiesis. Notch1 is an essential gene involved in the commitment and development of the T-cell lineage. However, the regulation of Notch1 in hematopoiesis is controversial, particularly at the level of hematopoietic stem cell (HSC). Here, we found that the expression of Notch1 is controlled at the post-transcriptional level in HSCs. HSCs express a considerable level of Notch1 mRNA, but its protein level is very low, suggesting a post-transcriptional suppression for Notch1. Using a retroviral sensor vector expressing a fusion mRNA of GFP and 3′ untranslated region (3′UTR) of a target gene, we demonstrated that the Notch1-3′UTR had a post-translational suppressive effect only at the HSC but not in the downstream progenitor stages. The sequence motif AUnA was required for this post-transcriptional regulation by the Notch1-3′UTR. Interestingly, this Notch1-3′UTR-mediated suppressive effect was relieved when HSCs were placed in the thymus, but not in the bone marrow. Thus, the expression of Notch1 in HSCs is regulated by microenvironment at the post-transcriptional level, which may control T lymphoid lineage commitment from HSCs.


Proceedings of the National Academy of Sciences of the United States of America | 2005

Developmental checkpoints of the basophil/mast cell lineages in adult murine hematopoiesis

Yojiro Arinobu; Hiromi Iwasaki; Michael F. Gurish; Shin-ichi Mizuno; Hirokazu Shigematsu; Hidetoshi Ozawa; Daniel G. Tenen; K. Frank Austen; Koichi Akashi


Genes & Development | 2006

The order of expression of transcription factors directs hierarchical specification of hematopoietic lineages

Hiromi Iwasaki; Shin-ichi Mizuno; Yojiro Arinobu; Hidetoshi Ozawa; Yasuo Mori; Hirokazu Shigematsu; Kiyoshi Takatsu; Daniel G. Tenen; Koichi Akashi


Archive | 2010

Leukemia stem cell markers

Fumihiko Ishikawa; Osamu Ohara; Yoriko Saito; Hiroshi Kitamura; Atsushi Hijikata; Hidetoshi Ozawa; Leonard D. Shultz


Archive | 2012

Procédé de sélection exclusive de l'adn circularisé à partir d'un adn monomoléculaire lors de la circularisation de molécules d'adn

Shin-ichi Mizuno; Hidetoshi Ozawa; Koji Nagafuji; Takashi Okamura


Blood | 2009

Development of Novel Stem Cell Transplantation and Gene-Immunotherapy Using WT1-Specific T-Cell Receptor Gene.

Toshiki Ochi; Hiroshi Fujiwara; Kozo Nagai; Toshiaki Shirakata; Kiyotaka Kuzushima; Sachiko Okamoto; Junichi Mineno; Hiroshi Shiku; Hidetoshi Ozawa; Fumihiko Ishikawa; Masaki Yasukawa


Blood | 2008

Notch1 Expression Is Regulated at Post-Transcriptional Level by 3′UTR Region in Hematopoietic Stem Cell Development

Shin-ichi Mizuno; Hidetoshi Ozawa; Tadafumi Iino; Yojiro Arinobu; Chong Yong; Hirokazu Shigematsu; Koichi Akashi


Blood | 2007

Human AML Stem Cells Remain Quiescent and Exhibit Chemotherapy Resistance within the Bone Marrow Endosteal Region.

Yoriko Saito; Shuro Yoshida; Noriyuki Saito; Mitsuhiro Fukata; Hidetoshi Ozawa; Takehiko Doi; Toshihiro Miyamoto; Koichi Ohshima; Naoyuki Uchida; Shuichi Taniguchi; Koichi Akashi; Mine Harada; Leonard D. Shultz; Fumihiko Ishikawa

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Leonard D. Shultz

University of Massachusetts Medical School

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Atsushi Hijikata

Nagahama Institute of Bio-Science and Technology

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