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- W2328482265 abstract "Chronic myelogenous leukemia (CML) is invariably associated with the expression of the p210 Bcr-Abl fusion protein. Although the Abl-encoded tyrosine kinase activity is important for leukemogenesis, the emerging problems of acquired resistance and minimal residual disease highlight the need for new complementary targets for pharmacological intervention. In our previous studies, we had identified a non-classical ubiquitin binding domain (UBD) within the NH2-terminal of p210 Bcr-Abl. Deletion of the UBD (p210 Bcr-Abl(≥UBD)) impairs the interaction between p210 Bcr-Abl and p-β-catenin (ser33). Over-expression of p210 Bcr-Abl, but not p210 Bcr-Abl(≥UBD), leads to an accumulation of phosphorylated β-catenin, and at least two of its known transcriptional targets, cyclin D1 and c-Myc. The interaction between p210 Bcr-Abl and β-catenin is ubiquitination dependent. β-catenin is a central component of the Wnt pathway which plays a critical role in the regulation of hematopoiesis. In a murine bone marrow transplantation model for CML, mice transplanted with hematopoietic cells that express p210 Bcr-Abl(≥UBD) have significantly increased life spans compared to mice transplanted with p210 Bcr-Abl expressing cells. Delayed disease progression is associated with decreased levels of β-catenin, and reduced numbers of granulocyte macrophage progenitors (GMPs), in the bone marrow. Deletion of UBD also impairs the transplantability of CML cells. Based on these observations we propose a model in which p210 Bcr-Abl may influence the Wnt signaling pathway, and leukemic expansion, by binding ubiquitinated β-catenin, and stabilizing it against degradation. Stabilized β-catenin leads to increased self-renewal of CML stem cells and progenitors. Importantly, this activity is contained within Bcr sequences, and is independent of tyrosine kinase activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2557. doi:1538-7445.AM2012-2557" @default.
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- W2328482265 date "2012-04-15" @default.
- W2328482265 modified "2023-09-22" @default.
- W2328482265 title "Abstract 2557: Exploring the contribution of ubiquitin binding domain of Bcr-Abl in chronic myelogenous leukemia" @default.
- W2328482265 doi "https://doi.org/10.1158/1538-7445.am2012-2557" @default.
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