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  • 1
    In: Leukemia & Lymphoma, Informa UK Limited, Vol. 49, No. 2 ( 2008-01), p. 342-345
    Type of Medium: Online Resource
    ISSN: 1042-8194 , 1029-2403
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2008
    detail.hit.zdb_id: 2030637-4
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  • 2
    Online Resource
    Online Resource
    Japanese Society of Internal Medicine ; 2005
    In:  Nihon Naika Gakkai Zasshi Vol. 94, No. 11 ( 2005), p. 2388-2390
    In: Nihon Naika Gakkai Zasshi, Japanese Society of Internal Medicine, Vol. 94, No. 11 ( 2005), p. 2388-2390
    Type of Medium: Online Resource
    ISSN: 0021-5384 , 1883-2083
    Language: English
    Publisher: Japanese Society of Internal Medicine
    Publication Date: 2005
    detail.hit.zdb_id: 2455995-7
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  • 3
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 173-173
    Abstract: ABO incompatibility between donor and recipient is not a barrier for successful allogeneic hematopoietic stem cell transplantation, but conflicting data still exist concerning its influence on transplant outcome, graft-versus-host disease (GVHD), relapse, and survival. We retrospectively analyzed the data of patients who underwent UR-BMT through the Japan Marrow Donor Program between January 1993 and September 2005, with complete data on ABO-blood group compatibility, age, and gender in donors and recipients. A total of 4,970 patients were transplanted with marrow from ABO-matched (M; n=2,513, 50.6%), major incompatible (MA; n=1,254, 25.2%), minor incompatible (MI; n=1,081, 21.8%), and bidirectional incompatible donors (IA; n=122, 2.5%), and were followed up over a median period of 325 days. Among these four groups, excluding age, there was no significant difference in the gender of patients and donors, number of transplantations, conditioning regimen, GVHD prophylaxis, and performance status before transplantation by the likelihood ratio test. The 5-year overall survival of any ABO-incompatible group was significantly lower compared to an identical group (Wilcoxon test, p 〈 0.0001); the estimates for each group were 50.0% (M), 44.7% (MA), 46.7% (MI), and 41.3% (IA). Even in HLA-matched transplantation (n=2,608), a similar difference in overall survival was observed among the four groups (p=0.0124). In ABO-mismatched transplantation, the processing of bone marrow is necessary to prevent hemolysis of donor or recipient red blood cells as a result of the infusion of ABO-incompatible red blood cells or plasma contained within it. This procedure may reduce the number of hematopoietic stem cells. In fact, the mean number of total infused cells in each group was 3.10 (M), 1.52 (MA), 2.87 (MI), and 1.33 (IA) x108 per patient body weight (kg), with a significant difference in 4,210 patients in which data on the infused cell number were available (M; n=2,310, MA; n=996, MI; n=802, IA; n=102). To examine whether the difference in overall survival depended on the transplanted cell number, we used time-dependent Cox proportional hazards modeling to compare identical and major incompatible groups in terms of overall survival. Whereas the disease (standard and high-risk malignant disease, and benign disease; p=0.0000), patient age (p=0.0000), and ABO compatibility (p=0.0311) were elucidated to be significant risk factors, the number of infused cells was not (p=0.0603). Engraftment of red blood cells, white blood cells, and platelets were significantly delayed in major ABO mismatch in comparison with ABO identity (p 〈 0.0001). Univariate analysis revealed a small but significant difference in the rate of grade III and IV GVHD among the four groups (p=0.0204). Patients with major and minor ABO incompatibility had a higher incidence of severe GVHD compared to ABO identity (21.9%, 20.4% vs 16.2%). There was no significant difference in GVHD of the skin and gut, but major and minor mismatch developed a higher incidence of moderate to severe hepatic GVHD compared to ABO match (p 〈 0.0001, p=0.0010, respectively). ABO incompatibility had no significant effect on relapse, but the incidence of rejection was significantly higher with ABO-incompatible transplantation (p=0.0219).
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
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  • 4
    In: Leukemia Research, Elsevier BV, Vol. 30, No. 6 ( 2006-6), p. 761-763
    Type of Medium: Online Resource
    ISSN: 0145-2126
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2006
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  • 5
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 4877-4877
    Abstract: The BCR/ABL fusion protein transforms hematopoietic stem cells and causes chronic myeloid leukemia (CML). However, the mechanism leading to the expansion of mature myeloid cells in CML remains obscure. To investigate this mechanism, we compared the gene expression profile of CML neutrophils with that of normal neutrophils by microarray analysis. The genes upregulated in CML neutrophils include critical transcription factors that regulate granulocytic differentiation and proliferation, as well as genes encoding neutrophil granule proteins (Table 1). The protein levels of these upregulated genes were also elevated in the CML neutrophils. To investigate whether BCR/ABL regulates the expression of these upregulated genes, primary CML neutrophils were exposed to 1 μM imatinib (a BCR/ABL tyrosine kinase inhibitor) for 12–16 hours. C/EBPα protein expression was downregulated in primary CML neutrophils after treatment with imatinib, compared to control cultures. We further explored the function of these upregulated genes in KCL22 cells, which are derived from CML blastic crisis. To investigate the effect of C/EBPα or C/EBPε on myeloid differentiation, we established KCL22 cells in which C/EBPα or C/EBPε expression was inducible (KCL22/α or KCL22/ε, respectively). Overexpression of either C/EBP protein resulted in morphological changes, such as reduction of the nuclear to cytoplasmic ratio, more condensed nuclear chromatin, and segmented nuclei, as well as the expression of differentiation specific markers including the G-CSF receptor and macrophage adhesion molecule-1 (Mac-1). These data indicate that C/EBPα /ε expression is sufficient to induce myeloid differentiation in BCR/ABL positive CML cells. We examined whether BCR/ABL regulates the protein expression of c-Myb. The expression of c-Myb in KCL22 cells treated with 1 μM imatinib was downregulated and growth in these cells decreased in parallel. Knock-down of c-Myb expression with siRNA inhibited the growth of KCL22 cells and these data indicate that c-Myb expression is important for the growth of CML cells. To test the effect of c-Myb on differentiation of KCL22 cells, we knocked down c-Myb expression with siRNA in KCL22/α or KCL22/ε cells after induction of C/EBP protein. The knock-down of c-Myb in KCL22α /ε cells resulted in downregulation of differentiation specific genes, including G-CSF receptor and neutophil elastase. Morphologically, the fraction of KCL22α /ε cells with segmented nuclei decreased when c-Myb expression was knocked down. Our results suggest that elevated expression of C/EBPα /ε and c-Myb play a key role in proliferation and differentiation in CML cells. Table 1. Genes Upregulated in CML Neutrophils. Description Gene transcription factor C/EBP α transcription factor C/EBP ε transcription factor c-Myb neutrophil granule protein lactoferrin neutrophil granule protein neutrophil elastase neutrophil granule protein lysozyme
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 1468538-3
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  • 6
    In: International Journal of Hematology, Springer Science and Business Media LLC, Vol. 87, No. 1 ( 2008-1), p. 83-87
    Type of Medium: Online Resource
    ISSN: 0925-5710 , 1865-3774
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2008
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  • 7
    Online Resource
    Online Resource
    American Society of Hematology ; 2006
    In:  Blood Vol. 108, No. 11 ( 2006-11-01), p. 2130-2130
    In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-01), p. 2130-2130
    Abstract: The BCR/ABL fusion protein transforms hematopoietic stem cells and causes chronic myeloid leukemia (CML). An increasing number of mature neutrophils is a characteristic feature in the chronic phase of CML. However, the mechanism by which stem cells transformed by Bcr/Abl differentiate mainly to mature neutrophils remains obscure. To investigate this mechanism, we compared the gene expression profile of CML neutrophils with that of normal neutrophils by microarray analysis. The genes encoding neutrophil granule proteins were upregulated in CML neutrophils, and C/EBPα and C/EBPε, critical transcription factors that regulate granulocytic differentiation, were also upregulated in these neutrophils. On the contrary, the expression of c-jun, a transcriptional factor that contributes to monopoiesis, was downregulated in CML neutrophils. Differences in the expressions of these genes were confirmed by quantitative RT-PCR. A BCR/ABL tyrosine kinase inhibitor, imatinib, released the downregulation of c-jun expression in primary CML neutrophils, showing that Bcr/Abl inhibited the expression of c-jun. Next, to explore the roles of these transcriptional factors in the chronic phase of CML, we established sublines of KCL22, a cell line derived from CML blastic crisis, in which C/EBPα or C/EBPε expression was inducible (KCL22/α or KCL22/ε respectively). Overexpression of either C/EBP protein resulted in morphological changes, such as a reduction of the nuclear to cytoplasmic ratio, more condensed nuclear chromatin, and segmented nuclei, as well as the expression of differentiation specific markers including G-CSF receptor. These data indicate that C/EBPα/ε expression is sufficient to induce myeloid differentiation in BCR/ABL-positive CML cells. Imatinib treatment released the down regulation of c-jun in KCL22, KCL22/α, and KCL22/ε cells in a manner similar to that in primary cells. Interestingly, imatinib induces monocytic differentiation of KCL22/α cells instead of granulocytic differentiation. This effect of imatinib is independent from C/EBPα induction in KCL22/α cells. The monocytic differentiation and the inhibition of granulocytic differentiation in KCL22/α cells were accompanied by c-jun upregulation. To investigate whether these effects on differentiation of KCL22/α cells depend on releasing the downregulation of c-jun expression with imatinib, we knocked down c-jun expression with siRNA in KCL22/α cells after induction of C/EBPα protein and with imatinib treatment. In the fraction of KCL22/α cells with segmented nuclei, the G-CSF receptor increased when c-jun expression was inhibited with siRNA, indicating that the level of c-jun expression controlled the differentiation fate of CML cells. These findings suggest that Bcr/Abl promotes neutrophil differentiation through downregulation of c-jun accompanied by elevated expressions of C/EBPα/ε.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2006
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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