| First Author | Fereshteh M | Year | 2012 |
| Journal | Proc Natl Acad Sci U S A | Volume | 109 |
| Issue | 31 | Pages | 12532-7 |
| PubMed ID | 22773819 | Mgi Jnum | J:188541 |
| Mgi Id | MGI:5440824 | Doi | 10.1073/pnas.1209815109 |
| Citation | Fereshteh M, et al. (2012) beta-Arrestin2 mediates the initiation and progression of myeloid leukemia. Proc Natl Acad Sci U S A 109(31):12532-7 |
| abstractText | beta-Arrestins were initially discovered as negative regulators of G protein-coupled receptor signaling. Although beta-arrestins have more recently been implicated as scaffold proteins that interact with various mitogenic and developmental signals, the genetic role of beta-arrestins in driving oncogenesis is not known. Here we have investigated the role of beta-arrestin in hematologic malignancies and have found that although both beta-arrestin1 and -2 are expressed in the hematopoietic system, loss of beta-arrestin2 preferentially leads to a severe impairment in the establishment and propagation of the chronic and blast crisis phases of chronic myelogenous leukemia (CML). These defects are linked to a reduced frequency, as well as defective self-renewal capacity of the cancer stem-cell population, in mouse models and in human CML patient samples. At a molecular level, the loss of beta-arrestin2 leads to a significant inhibition of beta-catenin stabilization, and ectopic activation of Wnt signaling reverses the defects observed in the beta-arrestin2 mutant cells. These data cumulatively show that beta-arrestin2 is essential for CML disease propagation and indicate that beta-arrestins and the Wnt/beta-catenin pathway lie in a signaling hierarchy in the context of CML cancer stem cell maintenance. |
