Loss of the xeroderma pigmentosum group B protein binding site impairs p210 BCR/ABL1 leukemogenic activity.

Previous studies have demonstrated that p210 BCR/ABL1 interacts directly with the xeroderma pigmentosum group B (XPB) protein, and that XPB is phosphorylated on tyrosine in cells that express p210 BCR/ABL1. In the current study, we have constructed a p210 BCR/ABL1 mutant that can no longer bind to XPB. The mutant has normal kinase activity and interacts with GRB2, but can no longer phosphorylate XPB.

Ubiquitin-mediated interaction of p210 BCR/ABL with β-catenin supports disease progression in a murine model for chronic myelogenous leukemia.

We have identified a ubiquitin-binding domain 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 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.

Contributions of the RhoGEF activity of p210 BCR/ABL to disease progression.

We have previously identified a tyrosine kinase-independent, guanine nucleotide exchange factor (GEF) activity, which is contained within the region of p210 no expansion BCR/ABL that distinguishes it from p190 BCR/ABL. In the current study, we have compared the transforming activity of p190 BCR/ABL, p210 BCR/ABL and a mutant that lacks GEF activity (p210 BCR/ABL(S509A)). In cell-based, ex vivo, and murine bone marrow transplantation (BMT) assays the transforming activity of p210 BCR/ABL(S509A) mimics p190 BCR/ABL, and is distinct from p210 BCR/ABL.