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  • 1
    Online Resource
    Online Resource
    A Novel BCL2-Driven Compound Mutant Mouse Model for In Vivo Research on BH3 Mimetics
    American Society of Hematology ; 2020
    In:  Blood Vol. 136, No. Supplement 1 ( 2020-11-5), p. 39-39
    Details
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 39-39
    Abstract: Introduction: Eµ-TCL1-transgenic mouse models are often applied to discover and observe the development and kinetic of chronic lymphocytic leukaemia (CLL), as they develop diseases most similar to human CLL with a very high penetrance. To gain a better understanding on new therapy options and their effect on disease regression it is very important to observe therapy response, overall survival and symptoms during treatment of the disease not only in vitro but also in vivo in a suitable mouse model. However, application of BH3 mimetics like venetoclax is limited in the classical Eµ-TCL1 mouse model, since these mice are resistant towards venetoclax treatment. Therefore, we have generated a novel mouse model with Eµ-TCL1 as back bone and conditional overexpression of BCL2. Methods and results: We established a new mouse model (TBC) by crossbreeding mice expressing Eµ-TCL1tg/wtwith mice containing a B-cell specific conditional Bcl-2Rosa26/wt; Cd19CreCre/wtoverexpression and compared the disease kinetics to classical Eµ-TCL1 mice and to BC mice. TBC animals exhibit a severe leukocytosis at very early stages of disease development (12 weeks; mean 96.000/µl) in comparison to TC (15.100/µl) and BC (81.900/µl) mice. TBC mice develop CD23low/CD21neg leukemic B cells as they are known from TC mice with CD19+/CD5+ expression. Indeed, these mice show a significantly shortened overall survival of ~300 days (n=43) compared to TC mice (n=106; ~350 days; p & lt;0.001) and BC mice (n=28; ~410 days; p & lt;0.001) with severe clinical symptoms such as splenomegaly and cachexia. Strikingly, in contrast classical TC mice, which are resistant towards venetoclax, isolated B-cells of TBC mice are 10-times more sensitive towards venetoclax in vitro (0,02 µM) and can also be killed by the MCL1 inhibitors in nanomolar ranges, but not by BCL-xl inhibitors ( & gt;2µM). Based on our in vitro data, we have treated TBC mice with venetoclax and observed an early and dramatic drop of leukocytes to normal ranges within the first two weeks of treatment. Leukocyte reduction lasted for the whole period of treatment. When investigating the spleens after sacrificing the mice they showed high amounts of dead cells inside the spleens, indicating that venetoclax was also efficient in lymphatic tissues as we know it from human trials. Conclusions: Autochthonous mouse models on which BH3 mimetics can be tested are rare. In our mouse model apoptosis screening in vitro we can show good results for BH3 mimetics with a high sensitivity already in low dosing. The BCL2-driven TCL1 mouse model enables the investigation of treatment with venetoclax in vivo to gain a better understanding of this frequently on patients applied therapy. Moreover, this model will help us to test other drugs (like MCL1 inhibitors) in combination with venetoclax to identify synergistic drugs in vivo in a timely manner. Furthermore, this model will offer us the opportunity to identify treatment strategies to overcome venetoclax resistance in vivo. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2020-142569
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 2
    Online Resource
    Online Resource
    FcmR Shapes BCR Signaling in IgM-Positive Leukemia
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 2620-2620
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 2620-2620
    Abstract: Background: The Fc receptor for IgM (FcmR/ TOSO) is significantly overexpressed on chronic lymphocytic leukemia (CLL) cells from peripheral blood, but becomes down-regulated in the tumor microenvironment by e.g. CD40:CD40L interaction. Since the functional role of FcmR on lymphomagenesis is still not understood, we developed a conditional knockout mouse with B cell-specific FcmR-depletion. These mice were crossbred with the Eµ-TCL1 murine model, which develops a CLL-like phenotype. Results: The depletion of FcmR/TOSO in TCL1 mice (Eµ-Tcl1tg/wt FcmRfl/fl CD19cre/wt; further on called TCT) revealed a significantly shorter overall survival (296 days; n=40) compared to the TOSO expressing control mice (Eµ-Tcl1tg/wt FcmRwt/wt CD19cre/wt; TC; 344 days; n=106; Log-rank p 〈 0.0001). In addition, these mice show a significantly higher blood leukocyte count and lower platelet and erythrocyte count. Leukocytes could be identified as CLL-characteristic leukemic CD19+/CD5+ B cells. Altogether TCT exhibited a faster progress of disease. Spleen immunohistochemistry revealed the transformation of most TCT (14/17 transformed) into an even more aggressive phenotype with increased splenomegaly and change in tissue and cell morphology compared to TC (9/9 not transformed). While characterizing these cells by flow cytometry, we identified a significantly higher expression of IgM on malignant B cells from TCT in comparison to TC mice. This finding indicates that the BCR itself might have a different contribution to lymphomagenesis in FcmR knock-out settings. Therefore, to validate the functional role of FcmR in the process of lymphomagenesis, we performed transcriptome profiling by RNA-Seq using splenic leukemic cells (CD19+ CD5+) from 36-week old TC (n=4) and TCT (n=4) mice. 2089 genes were found to be significantly modulated in the malignant cells of TCT mice, from which 1221 were downregulated and 868 showed an upregulation (significant change in mean expression; p 〈 0.05). To investigate the role of IgM on TCT mice, purified malignant B cells were incubated for two hours with F(ab')2 goat anti-mouse IgM. Strikingly, TCT mice showed 3941 genes (2054 downregulated, 1887 upregulated) with significant difference in expression compared to TC (p 〈 0.05). The gene expression profiles of the anti-IgM treated mice revealed a stronger regulation of BCR signalling in TCT mice, suggesting that FcmR represents an important factor in these processes. We examined the gene expression profiles, using Ingenuity Pathway Analysis Software. Analysis revealed that the most deregulated functions include interferon-signalling, recruitment of leukocytes, infection of cells and cellular movement. Conclusion: Here we present functional evidence that loss of FcmR results in increased IgM/BCR on the surface of non-switched leukemia. Moreover, malignant cells with loss of FcmR are more susceptible to BCR stimulation and show a signature of signalling pathways, which contribute to inflammation in B cell malignancies. Disclosures Fingerle-Rowson: MorphoSys: Employment. Pallasch:Gilead: Research Funding. Wendtner:Abbvie: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Genetech: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding; MorphoSys: Consultancy, Honoraria, Other: travel support, Research Funding; Roche: Consultancy, Honoraria, Other: travel support, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-118352
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
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    Online Resource
    Characteristics, outcomes and health care utilization of patients with acute myeloid leukemia aged 70 years or older: A single‐center retrospective analysis
    Wiley ; 2024
    In:  Hematological Oncology Vol. 42, No. 5 ( 2024-09)
    Details
    In: Hematological Oncology, Wiley, Vol. 42, No. 5 ( 2024-09)
    Abstract: The overall prognosis of older patients with acute myeloid leukemia (AML) is dismal. Only a small subgroup experiences long‐term survival. The discrimination between patients who are candidates for potentially curative approaches and those who are not is crucial since ‐ in addition to differences in terms of AML‐directed treatment ‐ different policies concerning intensive care unit (ICU) admission and involvement of specialized palliative care (SPC) seem obvious. To shed more light on characteristics, outcomes and health care utilization of older individuals with AML, we conducted an analysis comprising 107 consecutive patients with newly diagnosed AML aged ≥70 years treated at an academic tertiary care center in Germany between 1 January 2015, and 31 December 2020. Median age was 75 years (range: 70–87 years); 45% of patients were female. The proportion of patients receiving intensive induction chemotherapy was 35%, 55% had low‐intensity treatment and 10% did not receive AML‐directed treatment or follow‐up ended before treatment initiation. At least one ICU admission was documented for 47% of patients; SPC was involved in 43% of cases. Median follow‐up was 199 days. The median overall survival (OS) was 2.5 months; the 1‐year OS rate was 16%. Among patients who died during observation, the median proportion of time spent in the hospital between AML diagnosis and death was 56%. The most common places of death were normal wards (31%) and the ICU (28%). Patients less frequently died in a palliative care unit (14%) or at home (12%). In summary, results of the present analysis confirm the unfavorable prognosis of older patients with AML despite intensive health care utilization. Future efforts in this patient group should aim at optimizing the balance between appropriate AML‐directed treatment on the one hand and health care utilization including ICU stays on the other hand.
    Type of Medium: Online Resource
    ISSN: 0278-0232 , 1099-1069
    URL: Issue
    URL: Article
    DOI: 10.1002/hon.v42.5
    DOI: 10.1002/hon.3300
    Language: English
    Publisher: Wiley
    Publication Date: 2024
    detail.hit.zdb_id: 2001443-0
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