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

Abstract

• p210 BCR/ABL interacts with b-catenin in the bone marrow transplantation model for chronic myelogenous leukemia.• Loss of the interaction results in an altered disease phenotype, suggesting a role for b-catenin in chronic phase disease.We have identified a ubiquitin-binding domain within the NH 2 -terminal sequences of p210 BCR/ABL and determined that the binding site co-localizes with the binding site for b-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 b-catenin-binding mutant, in hematopoietic cells is associated with the accumulation of p-b-catenin (Tyr654) and increased TCF/LEF-mediated transcription. In a bone marrow transplantation model, the interaction between b-catenin and p-b-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 b-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 b-catenin and altering its transcriptional activity. They further suggest that the interaction may play a role in chronic phase disease progression. (Blood. 2013;122(12):2114-2124

Celecoxib inhibits proliferation and survival of chronic myelogeous leukemia (CML) cells via AMPK-dependent regulation of β-catenin and mTORC1/2

“…CML stem cells appear to rely, among others, on the β-catenin/Tcf-Lef-dependent transcription program [16]. This pathway is aberrantly activated in CML mononuclear cells both in the chronic phase and the blast crisis stage [17].…”

“…A great deal of attention has recently been paid to the role of signal transduction pathways involved in maintaining the self-renewal of leukemic cells. CML stem cells appear to rely, among others, on the β-catenin/Tcf-Lef-dependent transcription program [ 16 ]. This pathway is aberrantly activated in CML mononuclear cells both in the chronic phase and the blast crisis stage [ 17 ].…”

Regulation of hematopoiesis by activators and inhibitors of Wnt signaling from the niche

“…CML is characterized by a chronic phase and a blast crisis and it was shown that β‐catenin is required for the progression from the chronic phase into blast crisis . Catenin activation in blast crisis may also be promoted by mis‐splicing of the upstream factor GSK‐3β, which may collaborate with increased BCR‐ABL–mediated pTyr654‐catenin phosphorylation . In addition, like in Hox‐A9/Meis1‐induced AML, activation of β‐catenin also promotes the self‐renewal properties of granulocytic progenitors (GMP) in CML …”