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. In a bone marrow transplantation 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 predominantly exhibit expansion of neutrophils, polycythemia, and increased lifespan. The increased disease latency is associated with expansion of megakaryocyte-erythrocyte progenitors, a decrease in common myeloid progenitors, 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.
Department of Microbiology and Molecular Genetics and New Jersey Medical School-University Hospital Cancer Center, University of Medicine and Dentistry of New Jersey, Newark, NJ.
Ru
R
Chen
Tinghui
T
Hu
Gwendolyn M
GM
Mahon
Ilona
I
Tala
Nicole L
NL
Pannucci
Harvey L
HL
Ozer
Ian P
IP
Whitehead
D000818:Animals; D001665:Binding Sites; D016026:Bone Marrow Transplantation; D002460:Cell Line; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry / Q000378:metabolism*; D016130:Immunophenotyping; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D051379:Mice; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D051820:TCF Transcription Factors; D025801:Ubiquitin; D051176:beta Catenin; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl