Chen R, Hu T, Mahon GM, Tala I, Pannucci NL, Ozer HL, Whitehead IP

We have identified a ubiquitin binding domain (UBD) within the NH2-terminal sequences of p210 BCR/ABL and determined that the binding site co-localizes with the binding site for β-catenin. The domain does not support the auto-or trans-kinase activity of p210 BCR/ABL, or its ability to interact with GRB2 and activate ERK1/2 ...

Read More

signaling. Expression of p210 BCR/ABL, but not a β-catenin binding mutant, in hematopoietic cells is associated with the accumulation of p-β-catenin(Tyr654), and increased TCF/LEF-mediated transcription. In a bone marrow transplantation (BMT) model, the interaction between β-catenin and p-β-catenin(Tyr654) is detectable in mice transplanted with p210 BCR/ABL, but not the mutant. Whereas mice transplanted with p210 BCR/ABL exhibit myeloid disease with expansion of monocytes and neutrophils, mice transplanted with the mutant exhibit predominant expansion of neutrophils, polycythemia, and increased lifespan. The increased disease latency is associated with expansion of megakaryocyte-erythrocyte progenitors (MEPs), a decrease in common myeloid progenitors (CMPs), and reduced β-catenin signaling, in the bone marrow of the diseased mice. These observations support a model in which p210 BCR/ABL may influence lineage-specific leukemic expansion by directly binding and phosphorylating β-catenin, and altering its transcriptional activity. They further suggest that the interaction may play a role in chronic phase disease progression.

Date: Aug. 15, 2013

View in: Pubmed Google Scholar

158169