Hirono Iriuchishima

Publications (5)40.13 Total impact

• Article: Neovascular niche for human myeloma cells in immunodeficient mouse bone.

  Hirono Iriuchishima, Keiyo Takubo, Yoshitaka Miyakawa, Ayako Nakamura-Ishizu, Yoshiteru Miyauchi, Nobuyuki Fujita, Kana Miyamoto, Takeshi Miyamoto, Eiji Ikeda, Masahiro Kizaki, Yoshihisa Nojima, Toshio Suda
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  ABSTRACT: The interaction with bone marrow (BM) plays a crucial role in pathophysiological features of multiple myeloma (MM), including cell proliferation, chemoresistance, and bone lesion progression. To characterize the MM-BM interactions, we utilized an in vivo experimental model for human MM in which a GFP-expressing human MM cell line is transplanted into NOG mice (the NOG-hMM model). Transplanted MM cells preferentially engrafted at the metaphyseal region of the BM endosteum and formed a complex with osteoblasts and osteoclasts. A subpopulation of MM cells expressed VE-cadherin after transplantation and formed endothelial-like structures in the BM. CD138(+) myeloma cells in the BM were reduced by p53-dependent apoptosis following administration of the nitrogen mustard derivative bendamustine to mice in the NOG-hMM model. Bendamustine maintained the osteoblast lining on the bone surface and protected extracellular matrix structures. Furthermore, bendamustine suppressed the growth of osteoclasts and mesenchymal cells in the NOG-hMM model. Since VE-cadherin(+) MM cells were chemoresistant, hypoxic, and HIF-2α-positive compared to the VE-cadherin(-) population, VE-cadherin induction might depend on the oxygenation status. The NOG-hMM model described here is a useful system to analyze the dynamics of MM pathophysiology, interactions of MM cells with other cellular compartments, and the utility of novel anti-MM therapies.
  PLoS ONE 01/2012; 7(2):e30557. · 4.09 Impact Factor
• Article: Ex vivo maintenance of hematopoietic stem cells by quiescence induction through Fbxw7α overexpression.

  Hirono Iriuchishima, Keiyo Takubo, Sahoko Matsuoka, Ichiro Onoyama, Keiichi I Nakayama, Yoshihisa Nojima, Toshio Suda
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  ABSTRACT: Cell-cycle quiescence in hematopoietic stem cells (HSCs) is essential for maintaining stemness by protecting cells from differentiation or senescence. F-box and WD-40 domain protein 7 (Fbxw7) maintains HSCs and suppresses leukemogenesis by mediating ubiquitin-dependent degradation of cell-cycle activators and oncoproteins. Fbxw7α was shown to be the preferentially expressed Fbxw7 isoform in primitive HSCs. Forced Fbxw7α expression in lineage marker Sca-1(+)c-Kit(+) cells led to cell-cycle dormancy by reducing the protein levels of the Fbxw7 substrates c-Myc, Notch1, and phosphorylated S6 (a key downstream element of mTOR). Hypoxia, an essential factor for HSC quiescence, suppressed c-Myc in an Fbxw7α-dependent manner. Fbxw7α-overexpressing lineage marker Sca-1(+)c-Kit(+) cells sustained high reconstitution capacities during in vitro culture. These data suggest that Fbxw7α sustains HSC dormancy through c-Myc, Notch1, and the mTOR pathways. The modulation of Fbxw7α expression or activity represents a promising new tool for ex vivo HSC maintenance.
  Blood 12/2010; 117(8):2373-7. · 9.90 Impact Factor
• Article: Regulation of the HIF-1alpha level is essential for hematopoietic stem cells.

  Keiyo Takubo, Nobuhito Goda, Wakako Yamada, Hirono Iriuchishima, Eiji Ikeda, Yoshiaki Kubota, Haruko Shima, Randall S Johnson, Atsushi Hirao, Makoto Suematsu, Toshio Suda
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  ABSTRACT: Hematopoietic stem cells (HSCs) are sustained in a specific microenvironment known as the stem cell niche. Mammalian HSCs are kept quiescent in the endosteal niche, a hypoxic zone of the bone marrow (BM). In this study, we show that normal HSCs maintain intracellular hypoxia and stabilize hypoxia-inducible factor-1alpha (HIF-1alpha) protein. In HIF-1alpha-deficient mice, the HSCs lost their cell cycle quiescence and HSC numbers decreased during various stress settings including bone marrow transplantation, myelosuppression, or aging, in a p16(Ink4a)/p19(Arf)-dependent manner. Overstabilization of HIF-1alpha by biallelic loss of an E3 ubiquitin ligase for HIF-1alpha (VHL) induced cell cycle quiescence in HSCs and their progenitors but resulted in an impairment in transplantation capacity. In contrast, monoallelic loss of VHL induced cell cycle quiescence and improved BM engraftment during bone marrow transplantation. These data indicate that HSCs maintain cell cycle quiescence through the precise regulation of HIF-1alpha levels.
  Cell stem cell 09/2010; 7(3):391-402. · 23.56 Impact Factor
• Article: [Chronic eosinophilic leukemia with symptoms resembling Budd-Chiari syndrome due to liver infiltration].

  Hirono Iriuchishima, Yoshiyuki Ogawa, Takumi Hoshino, Takatomo Yoshida, Ken Sato, Hitoshi Takagi, Kotaro Toyama, Norifumi Tsukamoto, Takahiro Jinbo
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  ABSTRACT: A 68-year-old woman was admitted to our hospital with severe ascites, hepatomegaly and hypereosinophilia. We initially suspected Budd-Chiari Syndrome (BCS), but that was ruled out after confirming the presence of no obstruction in the major veins. A molecular biologic examination proved the clonality of the eosinophils and she was therefore diagnosed as having chronic eosinophilic leukemia (CEL). The pathologic findings of a liver biopsy showed dilation of the sinusoids with infiltration of eosinophils, portal eosinophilic infiltrations with fibrosis, and biliary damage. These findings thus suggested infiltration of the liver by the CEL. A relationship between myeloproliferative disorders and BCS has been commonly reported, however there have so far been very few reports which describe the pathology of CEL liver infiltrates. As a result, the present case in which CEL occurred while demonstrating symptoms and findings similar to BCS is therefore considered to be extremely rare. Further accumulation of such cases should therefore be carried out in the future.
  [Rinshō ketsueki] The Japanese journal of clinical hematology 07/2007; 48(6):505-9.
• Article: Presentation of extramedullary Philadelphia chromosome-positive biphenotypic acute leukemia as testicular mass: Response to imatinib-combined chemotherapy.

  Takayuki Saitoh, Takafumi Matsushima, Hirono Iriuchishima, Arito Yamane, Hiroyuki Irisawa, Hiroshi Handa, Norifumi Tsukamoto, Masamitsu Karasawa, Yoshihisa Nojima, Hirokazu Murakami
  Leukemia and Lymphoma 01/2007; 47(12):2667-9. · 2.58 Impact Factor