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

被引:3
|
作者
Chen, Ru
Hu, Tinghui
Mahon, Gwendolyn M.
Tala, Ilona
Pannucci, Nicole L.
Ozer, Harvey L.
Whitehead, Ian P.
机构
[1] Univ Med & Dent New Jersey, Dept Microbiol & Mol Genet, Newark, NJ 07103 USA
[2] Univ Med & Dent New Jersey, New Jersey Med Sch, Univ Hosp Canc Ctr, Newark, NJ 07103 USA
关键词
HEMATOPOIETIC STEM-CELLS; CHRONIC MYELOID-LEUKEMIA; MYELOPROLIFERATIVE DISEASE; SORTING COMPLEX; BCR; ONCOGENE; DOMAIN; MICE; PROTEIN; TRANSFORMATION;
D O I
10.1182/blood-2013-01-481184
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 beta-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 beta-catenin-binding mutant, in hematopoietic cells is associated with the accumulation of p-beta-catenin (Tyr654) and increased TCF/LEF-mediated transcription. In a bone marrow transplantation model, the interaction between beta-catenin and p-beta-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 beta-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 beta-catenin and altering its transcriptional activity. They further suggest that the interaction may play a role in chronic phase disease progression.
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页码:2114 / 2124
页数:11
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