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  • 1
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    A Novel β-catenin Inhibitor, AV65 Suppresses the Growth of CML Cell Lines Which Acquire Imatinib-Resistance Because of Abl Kinase Domain Mutations Including T315I and Hypoxia-Adaptation.
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 1081-1081
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 1081-1081
    Abstract: Imatinib and the second-generation ABL tyrosine kinase inhibitors (TKIs) such as dasatinib and nilotinib have dramatically changed the management of CML. However, these agents are effective neither for CML cells harboring T315I mutation nor for CML stem cells. Genetic analysis of blasts from CML patients in blast crisis has identified numerous members of the Wnt/b-catenin pathway as being activated (Radich et al, PNAS 2006) and loss of b-catenin has been reported to impair the renewal of CML stem cells (Chao et al, Cancer Cell 2007). Thus, b-catenin signaling inhibition may be useful for CML treatment. We herein describe the effects of a novel b-catenin inhibitor, AV65 on various imatinib-sensitive and –resistant CML cell lines (Table 1). Eight imatinib-sensitive human CML cell lines and one normal cell line derived from hepatocyte were exposed to AV65 for 72 hours and its anti-proliferative effects were examined by MTT assay. AV65 induced apoptosis in these CML cell lines time- and does-dependent manners and inhibited the growth of all eight CML cell lines with IC50 at ranging from 9.8 to 33.1nM. While that for hepatocyte was 204.8nM. Interestingly, AV65 induced polyploidies in K562 but not in BV173. In addition, AV65 augmented the anti-proliferative effects of imatinib additively against K562 and BV173. These findings suggested that AV65 alone or the combination with imatinib was effective for imatinib-sensitive CML cells. To investigated the effects of AV65 against imatinib-resistant CML cells, four imatinib-resistant CML cell lines such as K562/IMR (bcr-abl amplification), MYL-R1 (LYN overexpression), KBM5/ STIR (harboring T315I) and K562/D1-9 (P-glycoprotein overexpression), and BaF3 cells expressing the wild type BCR-ABL or its ten different mutant BCR-ABL forms including T315I, were used. There was little difference on the induction of apoptosis and anti-proliferative effects of AV65 except K562/D1-9 between each parental cell line and its resistant clone and AV65 inhibited the growth of all examined BaF3 cells harboring various mutations including T315I with IC50 at ranging from 21.6 to 46.5nM. IC50 values of AV65 for K562 and K562/D1-9 were 11.0 and 60.1nM, respectively. These findings suggested that the effects of AV65 were independent either to BCR-ABL expression level, ABL mutations or LYN overexpression, but might be affected by P-glycoprotein. Next, the effects of AV65 against the hypoxia-adapted CML cell lines such as K562/ HA and KCL22/HA were also investigated. These cell lines were resistant to imatinib, dasatinib, INNO-406 (another second-generation ABL TKI; Kimura et al, Blood 2005) and alkylating agents via the up-regulation of glyoxalase-I, a detoxification enzyme for the cytotoxic byproducts of glycolysis. Intriguingly, AV65 inhibited the growth of hypoxiaadapted CML cell lines at almost same concentration compared with their parental cell lines. Although CML stem cell niche has not been definitely identified, it might located in hypoxia because the inoculated human leukemia cells to immunodeficient mice preferably localized on the surface of osteoblasts in the epiphysis (Ninomiya et al, Leukemia 2007) where could be hypoxic. Taken together, AV65 may be effective for CML stem cells in hypoxia. In conclusion, AV65 inhibited the growth of CML cell lines which acquire imatinib-resistance because of Abl kinase domain mutations including T315I and hypoxiaadaptation. Therefore, AV65 may become a promising agent for CML treatment including both imatinib and the second-generation Abl TKIs-resistant patients. Figure
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.1081.1081
    RVK:
    XA 33000
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 2
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    Roles of Osteoclasts in Leukemic Cells
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 3184-3184
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 3184-3184
    Abstract: We have previously reported that zoledoronic acid (ZOL) augmented the in vivo effect of imatinib in a murine chronic myeloid leukemia (CML) model (Blood 2003). ZOL alone induces apoptosis in leukemic cells in vitro by inhibiting prenylation of the Ras-related proteins. In addition to this direct anti-leukemic effect, we hypothesized that ZOL also has some influence in leukemic cells in vivo indirectly by destroying osteoclasts (OCs), which is the primary therapeutic activity of ZOL in osteoporosis patients. Supporting this notion is that by mediating bone resorption, OCs release a variety of cytokines such as IGF- 1, TGF-β, etc. that have accumulated in the bone matrix. It has been reported that OCs play an important role in bone metastasis of solid tumor, especially in cancer stem cells. However, little is known about the role of OCs in leukemia. Therefore, we investigated it in vitro and in vivo. For this purpose, we established an in vitro osteoblasts (OBs) and OCs co-culture system. The stable co-culture system that we developed includes collagen gel and murine primary OBs and OCs. In addition, murine femoral bone sections were sometimes added to this culture system so that the OCs could release the cytokines from the bone matrix. Thus, the collagen gel and OBs were placed in 12-well plates with and without bone sections and/or OCs. The transwell chambers over the wells then received 1×104 Ba/F3 cells that had been transfected with wild type bcr-abl (Ba/F3/bcr-abl cells). OBs markedly enhanced the growth of Ba/F3/bcr-abl cells in this indirect contact coculture system whereas the presence of both OBs and OCs slightly suppressed cell growth. Intriguingly, when bone sections were added (OBs+OCs+bone), Ba/F3/bcr-abl cell proliferation was significantly suppressed compared to the effect of OBs alone or OBs+OCs (Figure). Cell cycle analysis revealed that the G0/G1 population was increased in Ba/F3/bcr-abl cells co-cultured with OBs+OCs+bones. We also observed that the p27 protein levels of Ba/F3/bcr-abl cells increased upon co-culture with OCs or OCs+bones, similar to their response to treatment with purified TGF-β. We performed ELISAs to determine the concentrations of cytokines in the supernatants of co-cultured OBs and OCs. There were higher levels of TGF-β1 in the OBs+OCs+bones supernatant than in the OBs+OCs supernatant. Furthermore, OBs produced high levels of IGF-1. These findings suggest that OBs and OCs affect the proliferation and the cell cycle arrest of leukemic cells by releasing soluble factors, respectively. To more comprehensively elucidate the roles OCs play in leukemia cells in vivo, we used reveromycin A (RM-A) which inhibits bone resorption by specifically inducing apoptosis in OCs (Woo et al, PNAS 2006). RM-A did not have any in vitro effects on the proliferation of Ba/F3/bcr-abl cells. Thus, we could know the unalloyed role of OCs in leukemia with RM-A compared with ZOL which inhibited directly both OCs and leukemic cells. Our preliminary data show that RM-A suppresses the engraftment of inoculated Ba/F3/bcr-abl cells to nude mice. We also present data from ongoing studies showing the effect of RM-A on leukemic cells in murine models. These findings suggested that OCs may be an important constituent of leukemia stem cell niche and destruction of OCs by either ZOL or RM-A is a novel strategy for leukemia treatment. Figure Figure
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.3184.3184
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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  • 3
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    Candidemia-Induced Emergency Granulopoiesis Consists of Successive Dual Waves Triggered by the Shift From C/EBPalpha to C/EBPbeta Dependency.
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 3778-3778
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 3778-3778
    Abstract: Abstract 3778 Introduction: Granulocyte is a major cellular component in the front line of host defense. The number of granulocytes must be tightly tuned to meet the demand, because both the shortage and the excess of granulocytes can be harmful to the host. During emergency situations such as infections, granulocytes are replenished from peripheral pools and bone marrow production. As the half-life of granulocytes is quite short, granulopoiesis, de novo production of granulocytes in bone marrow, plays an important role during emergency. We have previously shown that granulopoiesis at steady state is largely dependent on a transcription factor, C/EBPalpha, whereas emergency granulopoiesis is dependent on C/EBPbeta (Hirai H, et al. Nature Immunol., 2006). However, the precise developmental stage where the shift from C/EBPalpha dependency to C/EBPbeta dependency takes place is almost unknown. The aim of this study is to dissect the process of granulopoiesis by a novel flow cytometric method and to elucidate the molecular mechanisms involved in the regulation of emergency granulopoiesis. Methods: 4 ≂ 106 cfu Candida albicans were intravenously injected to induce emergency granulopoiesis. Mouse bone marrow cells were harvested and stained with a combination of fluorescent-conjugated antibodies including anti-c-kit, anti-CD34, anti-Ly6G antibodies and markers for other lineages. Then the stained cells were analyzed or sorted by flow cytometry. After eliminating the cells which lost potential to give rise to granulocytes, the remaining cells were dissected into five subpopulations (#1≂ #5) according to the expression levels of c-kit and Ly6G. #1 is c-kithigh Ly6Glow cells, @ #2: c-kitint Ly6Glow, #5: c-kitlow Ly6Ghigh, and the cells residing between #2 and #5 are divided into #3 and #4. Cell number, gene expressions and cell cycle status of each population were analyzed before and after inducing emergency granulopoiesis. @ Results and Discussions: Wright-Giemsa staining and qRT-PCR for granule proteins (cathepsin G, myeloperoxidase, neutrophil elastase2, lactoferrin and MMP9) in each population indicated that lower c-kit expression and higher Ly6G expression correlated well with granulocytic differentiation and that the granulopoiesis progresses from # 1 to #5 in this order both at steady state and during emergencies (Figure 1). Then we applied this method to candidemia-induced emergency granulopoiesis. In vivo BrdU incorporation analysis showed immediate acceleration of the cell cycle in the most immature population (#1) and in one of the intermediate populations (#2). Chronological monitoring of each population after inducing candidemia revealed that rapid increase in mature granulocytes (#5) preceded the replenishment from the most immature population (#1). These results suggested that there are two distinct gwavesh in granulopoiesis at the early phase of infection, a rapid supply (first gwaveh) of granulocytes from relatively mature population (#2≂ #4), and a further and sustained supply (second gwaveh) originated from more immature populations (#1) including hematopoietic stem/progenitor cells (Figure 1). Transcripts of C/EBPalpha were significantly downregulated in #1≂ #4 at the early phase of infection, while those of C/EBPbeta were maintained in all the subpopulation (Figure 2), suggesting that shift from C/EBPalpha dependency to C/EBPbeta dependency took place at multiple developmental steps in granulopoiesis. C/EBPbeta has less inhibitory effects on cell cycle than C/EBPalpha while their abilities to induce granulocytic differentiation are similar (Hirai H, et al. Nature Immunol., 2006). The shift toward C/EBPbeta dependency may trigger the dual waves in emergency granulopoiesis, which demands both differentiation and proliferation of granulocytic precursors. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.3778.3778
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 4
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    Expression of C/EBPβ in Bone Marrow Mesenchymal Stem Cells Is Mandatory for Early-Stage B Cell Lymphopoiesis
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 3457-3457
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    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 3457-3457
    Abstract: Abstract 3457 The interplay between hematopoietic cells and bone marrow microenvironment organized by mesenchymal stem cells is important for the maintenance of hematopoiesis. With respect to B cell lymphopoiesis, several constituents of bone marrow microenvironment specific for B cells (“B cell niche”) have been identified, including CXCL12/stromal cell-derived factor-1 (SDF-1)-abundant reticular cells as cellular factors, and CXCL12/SDF-1, interleukin (IL)-7, stem cell factor (SCF), fms-related tyrosine kinase 3 ligand (Flt3-L), and nuclear factor kappa-B ligand (RANKL), as essential humoral factors. However, the precise mechanism through which mesenchymal stem cells in the bone marrow microenvironment support B cell lymphopoiesis, especially the role of transcription factors, remains unknown. We show that the mesenchymal stem cells lacking a transcription factor, CCAAT enhancer binding protein (C/EBP) b, are functionally abnormal, which contribute to the impairment of B cell lymphopoiesis in C/EBPb knockout mice. In C/EBPb knockout mice, the number of B cells, in particular, B220+CD43+ precursor B cells, was significantly decreased in bone marrow compared with that in wild-type littermates (Figure 1A and 1B). As shown in Fig. 1A, the percentage of total B220+ B cells was decreased at 19.1 ± 7.1% in the bone marrow of C/EBPb knockout mice (KO, n = 13) compared to wild-type mice (WT, n = 14, 26.5 ± 7.3%: *P 〈 0.05). The percentage of B220+CD43+ precursor B cells was also decreased at 5.2 ± 1.5% in the bone marrow of C/EBPb knockout mice (KO, n = 13) compared to wild-type mice (WT, n = 14, 7.4 ± 1.6%: **P 〈 0.01). Intriguingly, in vivo bone marrow transplantation experiments demonstrated that the bone marrow cells derived from C/EBPb knockout mice were engrafted in lethally-irradiated (10 Gy) wild-type mice with equivalently B cell recovery compared to the bone marrow cells from normal wild-type mice. Conversely, when normal wild-type c-kit+ Sca-1+ lineages− hematopoietic stem cells (KSL cells) were co-cultured with C/EBPb deficient mesenchymal stem cells in vitro (KO), they showed impaired B cell differentiation compared to the co-culture with normal wild-type mesenchymal stem cells (WT, Figure 1C). Mechanistically, the CXCL12/SDF-1 production by C/EBPb deficient mesenchymal stem cells was reduced compared with that by wild-type mesenchymal stem cells (KO, n = 5, 4.47 ± 1.16 ng/mL; WT, n = 5, 9.90 ± 1.93 ng/mL; **P 〈 0.01). These results suggest a possibility that abnormal C/EBPƒÀ deficient mesenchymal stem cells in bone marrow microenvironment contribute to impaired B cell lymphopoiesis in C/EBPb knockout mice. We further found that C/EBPb deficient mesenchymal stem cells displayed several functional abnormalities. First, calcium accumulation was significantly reduced in 4 week osteogenesis-inducing cultures of C/EBPb-deficient mesenchymal stem cells compared to cultures of wild-type mesenchymal stem cells. This occurred along with the down-regulated expression of the principal osteogenic master molecule runt-related transcription factor 2 (Runx2). Second, lipid deposition was significantly reduced in 1 week adipogenesis-inducing cultures of C/EBPb-deficient mesenchymal stem cells. The expression of adipogenic markers, including peroxisome proliferator-activated receptor b (PPARb) was significantly reduced in adipogenic cultures of C/EBPb-deficient mesenchymal stem cells compared with cultures of wild-type mesenchymal stem cells Finally, the number of colony-forming unit fibroblast (CFU-F) was higher in the bone marrow of C/EBPb knockout mice than in that of wild-type mice. Collectively, C/EBPb-deficient mesenchymal stem cells have aberrant multi-differentiation capability and increased proliferation activity compared with wild-type mesenchymal stem cells, further supporting that C/EBPb-deficient mesenchymal stem cells were functionally abnormal. Altogether, this work demonstrates that impaired B cell lymphopoiesis in C/EBPb knockout mice is attributed to abnormal mesenchymal stem cells in bone marrow microenvironment, at least in a steady-state, an effect that is due in part to the impaired CXCL12/SDF-1 production. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.3457.3457
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 5
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    Osteoclasts Are Involved in the Maintenance of Dormant Leukemic Cells.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 4245-4245
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    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 4245-4245
    Abstract: Abstract 4245 We have previously reported that zoledronic acid (ZOL) had the anti-tumor activity against chronic myelogenous leukemia in the murine models and it could induce apoptosis to leukemic cells (Kuroda, et al. Blood, 2003). ZOL is a widely used agent to treat osteoporosis or hypercalcemia of malignancy because of its activity to induce apoptosis to osteoclasts (OCs), which are specialized cells to resorb the bone matrix. In this study, we hypothesized that OCs might be involved in the survival or the proliferation of leukemic cells in the bone marrow (BM) microenvironment which consists of osteoblasts (OBs), OCs, blood vessels, and so on. In order to verify our hypothesis, we used the in vitro co-culture system. Ba/F3 wt bcr-abl cells were indirectly co-cultured with the murine OBs, OCs, and/or the bone slices derived from the murine femoral bones in the transwell chambers. OBs and OCs enhanced the proliferation of Ba/F3 wt bcr-abl cells. Interestingly, OCs significantly suppressed the proliferation of Ba/F3 wt bcr-abl cells in the presence of the bone slices. Next, we examined the cell cycle status of Ba/F3 wt bcr-abl cells co-cultured in each condition. Ki-67-negative populations were reported to be in G0 phase, thus 7-AAD and Ki-67 double staining can distinguish population in G0 phase from that in G1 phase. It was revealed that OCs with bone slices increased the Ki-67-negative dormant populations in co-cultured Ba/F3 wt bcr-abl cells. Recently, it has been reported that TGF-β1 is a candidate cytokine that maintain the hibernation state of hematopoietic stem cells in the BM niche. Furthermore, TGF-β1 is one of the major cytokines accumulated in the mineralized bone matrix. Thus we evaluate the TGF-β1 levels in the culture supernatants of OBs, OCs, and/or bone slices by ELISA. The concentrations of TGF-β1 were significantly higher in the supernatants of OBs, OCs, and bone slices, thus it might be suggested that TGF-β1 was released from the bone slices by bone-resorbing OCs (Figure). Furthermore, TGF-β-neutralizing antibody reduced Ki-67-negative dormant populations in Ba/F3 wt bcr-abl cells co-cultured with OBs, OCs, and bone slices. In conclusion, our in vitro data demonstrate that OCs might maintain the dormant population of leukemic cells in the BM microenvironment and this effect was yielded, in part, by TGF-β1 released from the bone matrix by OCs. It was also suggested that OCs could be an effective target of a novel therapy against minimal residual disease of leukemia, which are thought to be resulted from the dormant population of leukemic cells residing in the BM microenvironment. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.4245.4245
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    XA 33000
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 6
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    Rakicidin A effectively induces apoptosis in hypoxia adapted Bcr-Abl positive leukemic cells
    Wiley ; 2011
    In:  Cancer Science Vol. 102, No. 3 ( 2011-03), p. 591-596
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    In: Cancer Science, Wiley, Vol. 102, No. 3 ( 2011-03), p. 591-596
    Type of Medium: Online Resource
    ISSN: 1347-9032
    URL: Issue
    URL: Article
    DOI: 10.1111/cas.2011.102.issue-3
    DOI: 10.1111/j.1349-7006.2010.01813.x
    Language: English
    Publisher: Wiley
    Publication Date: 2011
    detail.hit.zdb_id: 2115647-5
    detail.hit.zdb_id: 2111204-6
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  • 7
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    Leukaemia hijacks a neural mechanism to invade the central nervous system
    Springer Science and Business Media LLC ; 2018
    In:  Nature Vol. 560, No. 7716 ( 2018-8), p. 55-60
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    In: Nature, Springer Science and Business Media LLC, Vol. 560, No. 7716 ( 2018-8), p. 55-60
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-018-0342-5
    RVK:
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    RVK:
    UA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
    detail.hit.zdb_id: 120714-3
    detail.hit.zdb_id: 1413423-8
    SSG: 11
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  • 8
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    Surface Analysis of Ag-Zn Alloys Corroded in H〈SUB〉2〈/SUB〉S Gas Atmospheres
    Japan Institute of Metals ; 1987
    In:  Journal of the Japan Institute of Metals and Materials Vol. 51, No. 1 ( 1987), p. 63-69
    Details
    In: Journal of the Japan Institute of Metals and Materials, Japan Institute of Metals, Vol. 51, No. 1 ( 1987), p. 63-69
    Type of Medium: Online Resource
    ISSN: 0021-4876 , 1880-6880
    Uniform Title: H〈SUB〉2〈/SUB〉Sガス雰囲気中で腐食したAg-Zn合金の表面解析
    URL: Article
    DOI: 10.2320/jinstmet1952.51.1_63
    Language: English , Japanese
    Publisher: Japan Institute of Metals
    Publication Date: 1987
    detail.hit.zdb_id: 2218481-8
    detail.hit.zdb_id: 3006476-4
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  • 9
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    Hypoxia-Adapted Myeloma Cells Possess Stem Cell Character
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 3088-3088
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 3088-3088
    Abstract: The prognosis of patients with multiple myeloma (MM) has been improved by the emergence of new molecular targeting agents including proteasome inhibitors and immunomodurating agents. Nevertheless, MM remains incurable at present because it is likely that MM stem cells are resistant to these targeting agents. Thus, it is important to further investigate the biology of MM stem cells to cure the MM patients. We have demonstrated that b-catenin is a novel and attractive target against MM (Ashihara et al. Clin Cancer Res, 2009; Yao et al. Blood Cancer J, 2011). We next investigate novel targets focused on the hypoxic bone marrow (BM) environment. BM is known to have low levels of oxygen, particularly at the epiphysis, which is distant form the BM arterial blood supply. Normal hematopoietic stem cells (HSCs) reside in this hypoxic epiphyseal region “niche”, and HSCs are protected from DNA damage induced by reactive oxygen species. We have previously found that chronic myelogenous leukemia (CML) cells engrafted in the BM survived and proliferated in the severely hypoxic environment and that these hypoxia-adapted (HA) leukemic cells acquired stem cell-like characters (Takeuchi et al. Cell Death Differ, 2010). In this study, we investigated the characteristics of hypoxia-adapted MM (HA-MM) cells. We first confirmed oxygen status in the BM of the MM cell-engrafted mice. Irradiated NOD/SCID mice were inoculated with 2 x 106 AMO-1 cells. After 2 or 4 weeks transplantation, we sacrificed mice and confirmed engraftment. The inoculated MM cells engrafted in the epiphysis in recipient mice after 2 weeks transplantation, and populated endosteum of epiphysis after 4 weeks. These MM cells were positive for pimonidazole, which specifically accumulated in hypoxic cells ( 〈 1.3% O2 concentration). These observations suggested that MM cells resided in the BM are hypoxic. We then established AMO-1, OPM-2, and IM-9 HA-MM cells cultured under hypoxic conditions (O2 1%). These HA cells can continue to proliferate in hypoxic conditions for more than six months. In flow cytometric analysis, the G0 fraction cells as well as side population fraction cells significantly increased in HA-MM cells compared with those in the parental MM cells. We next transplanted parental or HA-MM AMO-1 cells with same cell numbers into irradiated NOD/SCID mice. The survival durations of mice transplanted with HA-AMO-1 cells were significantly shorter than that of mice transplanted with parental cells. Moreover, in serial transplantation experiments, all 5 HA-MM cell-transplanted mice died of MM whereas 1 out of 5 parental MM cell-transplanted mice (Figure 1). Quantitative RT-PCR analysis demonstrated that Sox2, Oct3, and Nanog mRNA transcripts increased in the HA-MM AMO-1 cells (Figure 2). We next investigated the signaling pathway activated in HA-MM cells. Interestingly, phosphorylated Smad2 expression was increased in HA-AMO-1 cells. These findings suggest that HA-MM cells possess stem cell-like character, and these cells may provide a useful model to investigate the mechanism of MM stem cells (myeloma-initiating cells) resistant to molecular target agents. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.3088.3088
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 10
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    Mitochondrial Protein Synthesis Is Essential for Terminal Differentiation of CD45– TER119–Erythroid and Lymphoid Progenitors
    Elsevier BV ; 2020
    In:  iScience Vol. 23, No. 11 ( 2020-11), p. 101654-
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    In: iScience, Elsevier BV, Vol. 23, No. 11 ( 2020-11), p. 101654-
    Type of Medium: Online Resource
    ISSN: 2589-0042
    URL: Article
    DOI: 10.1016/j.isci.2020.101654
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 2927064-9
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