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- W2016752309 abstract "Notch is activated by somatic mutation in more than 50% of cases of T‐cell acute lymphoblastic lymphoma/leukemia (T‐ALL). Exuberant notch signaling drives several oncogenic phenotypes, including enhanced proliferation, improved survival, and impaired differentiation. Inhibition of Notch is likely to yield improved treatment strategies for this disease and certain other malignancies, as well. However, because global inhibition of Notch may have intolerable toxicities, efforts are underway to identify the key downstream mediators of its neoplastic effects. We find that the clathrin‐mediated receptor uptake adapter Hrb (HIV‐rev binding protein) is a downstream target of Notch1. Hrb protein was induced to high levels by retroviral‐mediated expression of constitutively active Notch (ICN1) in bone marrow stem cells and T cell precursors in vitro. To explore a potential role for Hrb downstream of Notch, we have examined the effects of ICN1 on bone marrow progenitor cells (BMPCs) from Hrb‐deficient mice. Wild type BMPCs transduced with ICN1 grew to higher density in culture than did Hrbdeficient cells. There was no difference in distribution in cell cycle phases, and proliferative rates appeared to be the same. However, we found a significant increase in apoptosis in Hrb‐deficient BMPCs in comparison to cells from littermate control mice. This increase in apoptosis could be reversed by reexpression of Hrb in the mutant cells, thus verifying that Hrb provides an enhanced survival signal to ICN1‐expressing bone marrow cells. Potential downstream mediators of this survival signaling cascade are currently being identified. Because resistance to apoptosis is a key feature of leukemic cells, we hypothesize that the pro‐survival effect of Hrb provides a portion of the oncogenic properties of Notch. Thus, because Hrb‐knockout mice have no evident phenotype, other than male sterility, Hrb may be a useful molecular target for therapy of Notch‐dependent malignancies, such as T‐ALL. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B23." @default.
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- W2016752309 date "2009-12-10" @default.
- W2016752309 modified "2023-09-26" @default.
- W2016752309 title "Abstract B23: Notch‐induced Hrb suppresses apoptosis in bone marrow stem cells" @default.
- W2016752309 doi "https://doi.org/10.1158/1535-7163.targ-09-b23" @default.
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