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  • Englisch  (3)
  • Medizin  (3)
  • 1
    Online-Ressource
    Online-Ressource
    American Society of Hematology ; 2021
    In:  Blood Vol. 138, No. Supplement 1 ( 2021-11-05), p. 3473-3473
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 3473-3473
    Kurzfassung: B-cell lymphoma 2 (BCL2) family proteins play an important role in the intrinsic mitochondrial apoptotic response. As such, selective small-molecule BCL2 inhibitor venetoclax has proven to be an effective therapeutic in hematologic malignancies including acute myeloid leukemia (AML). The biggest pitfall of venetoclax, however, is that here is no clear biomarker that can readily predict its response. Discovery of molecular markers for response prediction based on genomics, BCL2 expression level, and anti-apoptotic protein level has not been successful so far. We hypothesized that venetoclax was essentially developed as a protein-protein interaction (PPI) drug, and since PPI is complexly involved in metabolic processes including post-translational modification of the corresponding protein, it is difficult to evaluate its level with genetic mutation or protein expression level. Therefore, in order to evaluate a PPI drug such as venetoclax, a study through direct PPI observation should be preceded, and changes in the PPI pathway that the PPI drug targets should be confirmed. Using single molecule co-immunoprecipitation technology, we sought to predict the status of each anti-apoptotic protein and identify the BCL2 related PPI, which is the main target of venetoclax. First, we tried to check whether the size of the PPI portion measured using the PPI probe is related to the reactivity of the BH3 mimetics of each sample. Based on the EC50 data obtained through treatment with venetoclax and AZD5991, the sample was divided into a sensitive group (EC50 & lt;300nM) and a resistance group with low reactivity (EC50 & gt;300nM), which were highly responsive to BH3 mimetics, and the difference in PPI between the two groups was analyzed. (Figure A) As a result of the analysis, it was confirmed that the BCL2 related profile, especially the BCL2 total lv and the BCL2 PPI, had a strong positive correlation with the venentoclax norm-AUC as initially predicted. (Figure B) Also, the level of the BCL2-BAX complex had a positive correlation with the venetoclax sensitivity, and these four types of profiles had a significantly higher correlation than the others. (Figure C) In the estimation process, models that do not fit known biology were excluded, and models with a low significance level were also excluded. As a result of estimation, it was confirmed that the model with the strongest predictive power was formed when 1) BCL2-BIMBH3 PPI, 2) BCL2-BAX complex, and 3) BCLxl-BAK complex were combined (Figure D, E). The accuracy of the model was r=0.87. The validation of the combination diagnosis model proceeded by tracking the PPI change of the primary bone marrow sample of patients who received venetoclax in clinic. Patient number BC7064 was classified as a high-BCL2 "responsive" group and was treated with venetoclax plus azacitidine. After stopping drug treatment, AML relapsed (BC7064-R) (Figure F). We conducted combination diagnosis on BC7064 and BC7064-R samples, and confirmed that the BCL2-BIMBH3 PPI decreased by half after relapse. In particular, the BCL2-BAX complex was no longer detected after relapse, and thus it could be predicted that BC7064-R will have significantly lower venetoclax responsiveness (Figure G). In conclusion, the combination diagnosis based on the BCL2 profile proposed by this research was made based on in vitro drug sensitivity, but it could also be applied to the actual clinical response results. In addition, this diagnostic method can sensitively track changes in the BCL2 profile throughout the AML treatment course, as seen in BC7064 case. Figure 1 Figure 1. Disclosures Koh: Pfizer: Consultancy; Jassen: Honoraria; AstraZeneca: Honoraria; Novartis: Honoraria; GSK: Honoraria; Roche: Honoraria; Takeda: Honoraria.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2021
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 2
    In: Experimental Neurology, Elsevier BV, Vol. 368 ( 2023-10), p. 114495-
    Materialart: Online-Ressource
    ISSN: 0014-4886
    RVK:
    Sprache: Englisch
    Verlag: Elsevier BV
    Publikationsdatum: 2023
    ZDB Id: 1466932-8
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 3
    Online-Ressource
    Online-Ressource
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 3 ( 2011-02-01), p. 884-894
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 3 ( 2011-02-01), p. 884-894
    Kurzfassung: Constitutive photomorphogenic 1 (COP1) is a p53-targeting E3 ubiquitin ligase that is downregulated by DNA damage through mechanisms that remain obscure. Here, we report that COP1 is not downregulated following DNA damage in 14-3-3σ null cells, implicating 14-3-3σ as a critical regulator in the response of COP1 to DNA damage. We also identified that 14-3-3σ, a p53 target gene product, interacted with COP1 and controlled COP1 protein stability after DNA damage. Mechanistic studies revealed that 14-3-3σ enhanced COP1 self-ubiquitination, thereby preventing COP1-mediated p53 ubiquitination, degradation, and transcriptional repression. In addition, we found that COP1 expression promoted cell proliferation, cell transformation, and tumor progression, manifesting its role in cancer promotion, whereas 14-3-3σ negatively regulated COP1 function and prevented tumor growth in a mouse xenograft model of human cancer. Immunohistochemical analysis of clinical breast and pancreatic cancer specimens demonstrated that COP1 protein levels were inversely correlated with 14-3-3σ protein levels. Together, our findings define a mechanism for posttranslational regulation of COP1 after DNA damage that can explain the correlation between COP1 overexpression and 14-3-3σ downregulation during tumorigenesis. Cancer Res; 71(3); 884–94. ©2010 AACR.
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2011
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
    Standort Signatur Einschränkungen Verfügbarkeit
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