Abstract 936: Ubiquitin-mediated interaction of p210 Bcr-Abl with β-catenin supports disease progression in a murine model for chronic myelogenous leukemia

Abstract

Abstract Chronic myelogenous leukemia (CML) is a malignant hematopoietic stem cell disorder that is invariably associated with the expression of the p210 Bcr-Abl fusion protein. Although the deregulated, Abl-encoded tyrosine kinase activity is essential for disease progression, several studies have shown that Bcr encoded sequences are also necessary for p210 Bcr-Abl-mediated leukemogenesis. We have identified a non-classical ubiquitin binding domain (UBD) within the NH2-terminal Bcr sequences of p210 Bcr-Abl. Deletion of the UBD (p210 Bcr-Abl(ΔUBD)) does not impair the auto-or trans-kinase activity of p210 Bcr-Abl, nor does it impair the ability of p210 Bcr-Abl to interact with Grb2 and activate Erk1/2 signaling. Although β-catenin has been previously identified as a binding partner for Bcr and Bcr-Abl, p210 Bcr-Abl(ΔUBD) does not interact with β-catenin. Treatment with an E1 inhibitor impairs the interaction between β-catenin and p210 Bcr-Abl, suggesting that the interaction is ubiquitin-dependent. Over-expression of p210 Bcr-Abl, but not p210 Bcr-Abl(ΔUBD), leads to an accumulation of phosphorylated β-catenin, and at least two of its known transcriptional targets, cyclin D1 and c-Myc. Hyper-phosphorylation of β-catenin cannot be attributed to increased activity of GSK-3β or Pin-1. In a murine bone marrow transplantation model for CML, mice transplanted with hematopoietic cells that express p210 Bcr-Abl(ΔUBD) 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. 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. 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 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 936. doi:10.1158/1538-7445.AM2011-936