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  • 1
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    Retraction: Depletion of pleckstrin homology domain leucine-rich repeat protein phosphatases 1 and 2 by Bcr-Abl promotes chronic myelogenous leukemia cell proliferation through continuous phosphorylation of Akt isoforms.
    Elsevier BV ; 2010
    In:  Journal of Biological Chemistry Vol. 285, No. 20 ( 2010-05), p. 15662-
    Details
    In: Journal of Biological Chemistry, Elsevier BV, Vol. 285, No. 20 ( 2010-05), p. 15662-
    Type of Medium: Online Resource
    ISSN: 0021-9258
    URL: Article
    DOI: 10.1074/jbc.A109.808182
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2010
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    SSG: 12
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  • 2
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    Induction of CABLES1 by the TKI Inhibits the Cell Cycle Progression and Induces Apoptosis In CML Cell.
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 1199-1199
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 1199-1199
    Abstract: Abstract 1199 [Background and Aims] CABLES1 (cyclin-dependent kinase (CDK)-5 and ABL enzyme 1) is a regulator of cell proliferation, apoptosis, and cell cycle, and it has been reported to be lost in a variety cancers. It has been also reported that knockout of the Cable1 gene has minimal to no effect on hematopoietic stem cells. However, we found that the expression of Cables1 gene and CABLES1 protein was suppressed in CML cells, and its function is little known in CML. In this study, we have investigated the function of CABLES1 in CML cell proliferation. [Methods] The cells used in this study were human CML cell lines, K562, Meg01 and SHG3 cells. Primary CML cells (ALDHhi cells) were obtained from the bone marrow of CML (CP) patients (n=12). Human normal ALDHhi cells were isolated from bone marrow of healthy volunteers after obtaining informed consents. For analysis of Cables1 mRNA expression, quantitative RT-PCR was performed in all cell lines treated with Abl kinase inhibitors (STI571, AMN107, and BMS354825). For cell survival analysis and the levels of p53 and some CDKIs in CML cells, MTT assays, western blot and cell cycle analysis were performed in all cell lines transfected with Cables1 shRNA or cDNA. For colony analysis, the colonies of CFU-GEMM, CFU-GM, and BFU-E were counted in CML stem/progenitor cells transfected with Cables1 cDNA or shiRNA, or treated with Abl kinase inhibitors. [Results] In CML cell lines, the expressions of Cables1 mRNA and CABLES1 protein were significantly increased by treatment with Abl kinase inhibitors or transfection with Bcr-Abl shRNA. In CML cells transfected with the Cables1 cDNA, it is shown that CML cell proliferation was inhibited, and the phosphorylation levels of p53, and the expression of BAX and p21 protein were markedly increased compared to the untransfected cells. In addition, the overexpression of CABLES1 induced G1 cell cycle arrest and reduced the DiOC6 fluorescence, indicating breakdown of the mitochondrial membrane potential in CML cells. On the other hand, the changes of p73 and p27 protein expression were not detected. Moreover, in CML cells transfected with Cables1 shRNA, the inhibition of CML cell proliferation by the Abl kinase inhibitors were weakened. In CML stem/progenitor cells (ALDHhi cells) obtained from patients with CML, the expression of Cables1 mRNA was suppressed, and the transfection with Bcr-Abl shRNA or treatment with Abl kinase inhibitors increased the expression of Cables1 mRNA and CABLES1 protein, and decreased the counts of CFU-GEMM, CFU-GM and BFU-E. [Conclusion] Our results demonstrated that the Bcr-Abl suppressed the expression of CABLES1, and the depletion of CABLES1 promotes cell cycle progression and p53-dependent apoptosis. Moreover, the induction of CABLES1 expression has the potentiality to eradicate CML stem/progenitor cells. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.1199.1199
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 3
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    Depletion of PHLPP1 and 2 by Bcr-Abl Promotes CML Cell Proliferation through the Continuous Phosphorylation of Akt.
    American Society of Hematology ; 2009
    In:  Blood Vol. 114, No. 22 ( 2009-11-20), p. 2182-2182
    Details
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 2182-2182
    Abstract: Abstract 2182 Poster Board II-159 Objective PHLPP1 and 2 (pleckstrin homology (PH) domain leucine-rich repeat protein phosphatase 1 and 2) is identified as the dephosphorylation enzyme of Akt, the same as that of PP2A of the dephosphorylation enzyme of Akt, and regulate the cell-growth signal of Akt through a dephosphorylation of the phosphorylated Akt (p-Akt). Previously, we reported the expression of PHLPP1 and 2 were suppressed in CML cell lines. In this study, we investigated the the CML and its progenitor cell proliferation through the phosphorylation of Akt by depletion of PHLPP1 and 2. Method CML cell lines (K562, Meg01, SHG3) and the CML clinical specimen (n= 10) were used for this research. The changes in the expression of PHLPP1 and 2 by treatment with Abl kinase inhibitors (STI571, AMN107 and BMS354825) or knock down with Bcr-Abl gene were evaluated by RT-PCR method. The influence on the expression of PHLPP1 and 2 in AML cell line transfected with Bcr-Abl also evaluated. CML progenitor cells derived from CML patients separated by ALDH activity, and the expression of PHLPP1 and 2 were investigated by quantitative RT-PCR method. p-Ser473 Akt1, 2 and 3 by Abl kinase inhibitor or knock down with PHLPP1 and 2 were measured, and the influence on the effect of cell growth inhibition by MTT assay. The expression of PHLPP1 and 2 and colony formation in colony forming unit-granulocyte, erythroid, macrophage, megakaryocyte (CFU-GEMM), colony forming unit-granulocyte, macrophage (CFU-GM) and burst forming unit-erythroid (BFU-E) derived from Bcr-Abl positive hematopoietic progenitor cells also evaluated. Result The expression of mRNA and protein of PHLPP1 and 2 were increased by treatment with Abl kinase inhibitor or Bcr-Abl knock down by siRNA in CML cell lines and AML cell line trasfected with Bcr-Abl gene. Moreover, p-Ser473 Akt 2 and 3 were decreased according to the expression of PHLPP1, and also p-Ser473 Akt1 and 3 according to the expression of PHLPP2. The Abl kinase inhibitors induced the expression of PHLPP1, 2 and the reduction of p-Ser473 Akt isoforms. The Abl kinase inhibitors inhibited the CML cell proliferation via the depletion of PHLPP1 and 2. In Bcr-Abl positive progenitor cells, the expression of PHLPP1 and 2 was increased, and colony formation was suppressed by Abl kinase inhibitor and by Bcr-Abl siRNA. The colony formation in progenitor cells knocked down PHLPP1 and 2 were decreased when treated with Abl kinase inhibitors. Conclusion These results suggest that Bcr-Abl might promote CML cell proliferarion through continuous phosphorylation of p-Ser473 Akt1, 2 and 3 by suppression of PHLPP1 and 2, and that the induction of PHLPP1 and 2 may be effective to regulate the cell proliferation in CML cells. It may be also that the induction of expression of PHLPPs has the potential possibility as the targets on the regulation of cell proliferation in Bcr-Abl positive progenitor cells. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V114.22.2182.2182
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 4
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    Elevation of Kinase Interacting with Stathmin (KIS) and Promotion of Cellcycle Progression by KIS in Leukemia Cells.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 1365-1365
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 1365-1365
    Abstract: Purpose: The protein p27 is an important regulator of cell cycle. An increase in p27 causes proliferation of cells, while a decrease in p27 induces quiescence of cells. p27 is regulated by transcriptional, translational and proteolytic mechanisms. Among them, an importnant mechanism in the regulation of p27 is proteolysis. Kinase interacting with stathmin, KIS, is a serine / threonine kinase, and regulates cell cycle progression through the phosphorylation of p27 on serine 10. The S10 phosphorylation on p27 plays an important role in p27 degradation. KIS that phosphorylates p27 on S10 and its role in the regulation of cell cycle progression have not been defined in leukemia cells. In this study, we investigated the role of KIS in leukemia cells. Materials and Methods: We examined the biological significance of KIS expression in K562, NB4, U937, CEM, MOLT4, and SUP-B15 leukemia cells and relationship with the G1 regulaters, such as p27. Moreover, we generated the lentivirus vector inserted with the dsDNA of KIS small interfering RNA (siRNA), and effects of down-regulation of KIS by siRNA transfection were investigated in leukemia cells. Results: RT-PCR and western blot analysis showed high KIS expression in all leukemia cells. The p27 phosphorylation on S10 was significantly lower in the leukemia cells transduced with KIS siRNA and depletion of KIS enhanced growth arrest. The down-regulation of KIS induced G1 arrest in cell cycle, but not apoptosis. In cell cycle analysis, control leukemia cells showed 42.3 ± 1.8 %, but leukemia cells transfected with KIS siRNA showed 67,1 ± 2.1 % in G1 fraction. Moreover, these cells significantly showed small population in S ansd G2 fractions compared compared with controls. Conclusion: These findings suggest KIS expression promotes cell cycle progression in leukemia cells. Depletion of KIS using siRNA in leukemia cells induced cell cycle arrest in G1 phase compared with control cells. In this study, we showed that KIS might be the target for the molecular therapy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.1365.1365
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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  • 5
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    Development as Anti-Leukemic Agents, a Novel Synthesis of Phospha Sugar Derivatives in Therapy for Leukemias, and Analysis of Their Characterizations.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 4174-4174
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 4174-4174
    Abstract: [Background] Sugar derivatives whose oxygen atom in the hemiacetal ring is replaced by a carbon, nitrogen, sulfur atom, and etc., are celled as pseudo sugars. The synthesis and bioassay of these pseudo sugars are well investigated and are known as potential bioactive materials. Phospha sugar, which is one of pseudo sugars, having a phosphorus atom instead of the oxygen atom in the hemiacetal ring, is little known. The synthesis and bioassay of phospha sugars are not well studied in detail. We synthesized the 2, 3, 4-tribromo-3-methyl-1-phenyl phospholane 1-oxide (TMPP) and 2, 3-dibromo-3-methyl-1-phenyl phospholane 1-oxide (DMPP) by the nucleophilic substitution reactions, and found their anti-leukemic activities. [Purpose] The aims of the present study were to evaluate the inhibition of proliferation and induction of apoptosis in leukemia cell treated with TMPP or DMPP, and define the target molecules for TMPP in leukemia cells. [Methods] The cells used in this study were human leukemia cell lines, K562, U937, and YRK2 cells. For proliferation analysis, MTT assays were performed in leukemia cells treated with TMPP. For cell cycle analysis, flow cytometory analysis was performed in leukemia cells treated with TMPP or DMPP by PI staining. For analysis of mitotic regulatory proteins (p27, p21, Skp2, Cdc25B, Cyclin D1, Survivin, and Aurora kinase B), Western blotting was perfo rmed in leukemia cells treated with TMPP. [Results] In leukemia cell lines, DMPP and TMPP significantly inhibited the cell proliferation, and TMPP more strongly inhibited the cell proliferation than DMPP. 10 μM TMPP significantly induced G2/M phase arrest, and 25 μM TMPP induced apoptosis in leukemia cells. In leukemia cells, 10 μM TMPP reduced protein of Aurora kinase B, Survivin, Cyclin D1, Skp2 KIS, and FoxM1, while increased protein expression of p21and p27 by western blot analysis. Moreover, 25 μM TMPP activated caspase-3 and caspase-9, cleaved PARP, and reduced Bcl-2. [Conclusions] In this study, we report in the first time the possibility of phospha sugar derivatives as anti-leukemic agents in therapy for leukemias, and analysis of their characterizations. DMPP significantly inhibited the proliferation, and induced apoptosis of leukemia cells. These results demonstrated that the FoxM1, which is an essential transcription factor for cell growth and regulates expression of the mitotic regulators, is one of the targets for DMPP. Therefore, DMPP or TMPP has possibility as new agents for FoxM1 in leukemia therapy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.4174.4174
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
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  • 6
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    Bcr-Abl Inhibitors Induce Expression of HoxA10, Playing a Role as an Inhibitor of the Proliferation through PI3K/PKB Pathway in Chronic Myelogenous Leukemia Cells.
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-16), p. 1363-1363
    Details
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 1363-1363
    Abstract: [Background] Homeobox (Hox) genes are grouped together in 4 clusters, A to D. Recent studies has shown that the Hox proteins are important in the control of differentiation and proliferation in hematopoietic cells. It is reported that HoxA10 has been expressed in all types acute myeloid leukemias (except for APL) but not in acute lymphoid leukemias, implicating an important role as a regulator of myeloid progenitors. Moreover, overexpression of HoxA10 induses the proliferation of early progenitor cells and leads to the development of myeloid leukemias. However, we found that Bcr-Abl inhibitors increased the expression of HoxA10 gene in CML cells. In this study, we investigated the mechanism controlling HoxA10 in CML cells treated with Bcr-Abl inhibitors. [Methods] The cells used in this study were Ph1 positive CML cells, K562 and Meg01, and U937 cells for a Ph1 negative cell. We used AMN107 and BMS354825 for Bcr-Abl inhibitors, LY294002 for a PI3K inhibitor, PP2 for a Src kinase inhibitor, and SB203580 for a p38 MAP kinase inhibitor. For analysis of HoxA10 mRNA and protein, RT-PCR and western blot were performed in K562, Meg-01 and U937 cells, which untreated or treated with AMN107, BMS354825, LY294002, PP2, or SB203580 respectively. We then attempted to localize the intracellular locations of HoxA10 in K562 and Meg01, which untreated or treated with AMN107, BMS354825, or LY294002 by using conforcal fluorescence microscopy. Finally, for analysis of proliferation in K562, Meg-01 and U937 transfected with siRNA HoxA10, MTT assays were performed in untransfected or transfected K562, Meg-01 and U937 treated with or without AMN107, BMS354825, orLY294002. [Results] Both K562 and Meg01 cells expressed HoxA10 mRNA and protein at lower level compared to U937 cells. Interestingly, treatment with AMN107, BMS354825, or LY294002 increased the expression of HoxA10 mRNA and protein in both K562 and Meg01 cells. In contrast, treatment with PP2 or SB203580 did not affect the expression of HoxA10 mRNA and protein in both K562 and Meg01 cells. The fluorescence of HoxA10 was more strongly observed in the area corresponding to the cell’s cytoplasm than nucleus, and the treatment with AMN107, BMS354825, or LY294002 increased the fluorescence in nucleus of K562 and Meg01 cells in a time-dependent manner. In K562 and Meg01 cells transfected with the siRNA HoxA10, treatment with AMN107 or BMS354825 slightly inhibited the proliferation compared to K562 and Meg01 transfected with control siRNA. [Conclusions] In this study, we showed that Bcr-Abl inhibitors induced the expression of HoxA10, and HoxA10 was regulated by PI3K/P[Kappa[B pathway in CML cells. This finding indicates a new insight in the regulation of cell proliferation via the PI3K/PKB signal pathway in CML cells.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V108.11.1363.1363
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
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  • 7
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    CMC‐544 (inotuzumab ozogamicin) shows less effect on multidrug resistant cells: analyses in cell lines and cells from patients with B‐cell chronic lymphocytic leukaemia and lymphoma
    Wiley ; 2009
    In:  British Journal of Haematology Vol. 146, No. 1 ( 2009-07), p. 34-43
    Details
    In: British Journal of Haematology, Wiley, Vol. 146, No. 1 ( 2009-07), p. 34-43
    Abstract: The effect of CMC‐544, a calicheamicin‐conjugated anti‐CD22 monoclonal antibody, was analysed in relation to CD22 and P‐glycoprotein (P‐gp) in B‐cell chronic lymphocytic leukaemia (CLL) and non‐Hodgkin lymphoma (NHL) in vitro . The cell lines used were CD22‐positive parental Daudi and Raji, and their P‐gp positive sublines, Daudi/MDR and Raji/MDR. Cells obtained from 19 patients with B‐cell CLL or NHL were also used. The effect of CMC‐544 was analysed by viable cell count, morphology, annexin‐V staining, and cell cycle distribution. A dose‐dependent, selective cytotoxic effect of CMC‐544 was observed in cell lines that expressed CD22. CMC‐544 was not effective on Daudi/MDR and Raji/MDR cells compared with their parental cells. The MDR modifiers, PSC833 and MS209, restored the cytotoxic effect of CMC‐544 in P‐gp‐expressing sublines. In clinical samples, the cytotoxic effect of CMC‐544 was inversely related to the amount of P‐gp ( P  = 0·003), and to intracellular rhodamine‐123 accumulation ( P   〈  0·001). On the other hand, the effect positively correlated with the amount of CD22 ( P  = 0·010). The effect of CMC‐544 depends on the levels of CD22 and P‐gp. Our findings will help to predict the clinical effectiveness of this drug on these B‐cell malignancies, suggesting a beneficial effect with combined use of CMC‐544 and MDR modifiers.
    Type of Medium: Online Resource
    ISSN: 0007-1048 , 1365-2141
    URL: Issue
    URL: Article
    DOI: 10.1111/bjh.2009.146.issue-1
    DOI: 10.1111/j.1365-2141.2009.07701.x
    RVK:
    XA 34100
    Language: English
    Publisher: Wiley
    Publication Date: 2009
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  • 8
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    KIS induces proliferation and the cell cycle progression through the phosphorylation of p27Kip1 in leukemia cells
    Elsevier BV ; 2008
    In:  Leukemia Research Vol. 32, No. 9 ( 2008-9), p. 1358-1365
    Details
    In: Leukemia Research, Elsevier BV, Vol. 32, No. 9 ( 2008-9), p. 1358-1365
    Type of Medium: Online Resource
    ISSN: 0145-2126
    URL: Article
    DOI: 10.1016/j.leukres.2008.02.012
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2008
    detail.hit.zdb_id: 2008028-1
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  • 9
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    Role for interleukin-6 and insulin-like growth factor-I via PI3-K/Akt pathway in the proliferation of CD56− and CD56+ multiple myeloma cells
    Elsevier BV ; 2006
    In:  Experimental Hematology Vol. 34, No. 6 ( 2006-06), p. 736-744
    Details
    In: Experimental Hematology, Elsevier BV, Vol. 34, No. 6 ( 2006-06), p. 736-744
    Type of Medium: Online Resource
    ISSN: 0301-472X
    URL: Article
    DOI: 10.1016/j.exphem.2006.02.012
    RVK:
    XA 42470
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2006
    detail.hit.zdb_id: 2005403-8
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  • 10
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    HOXA10 expression induced by Abl kinase inhibitors enhanced apoptosis through PI3K pathway in CML cells
    Elsevier BV ; 2008
    In:  Leukemia Research Vol. 32, No. 6 ( 2008-6), p. 962-971
    Details
    In: Leukemia Research, Elsevier BV, Vol. 32, No. 6 ( 2008-6), p. 962-971
    Type of Medium: Online Resource
    ISSN: 0145-2126
    URL: Article
    DOI: 10.1016/j.leukres.2007.11.034
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2008
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