β-Arrestin2 mediates the initiation and progression of myeloid leukemia

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-07, Vol.109 (31), p.12532-12537
• Main Authors: Fereshteh, Mark, Ito, Takahiro, Kovacs, Jeffrey J, Zhao, Chen, Kwon, Hyog Young, Tornini, Valerie, Konuma, Takaaki, Chen, Minyong, Lefkowitz, Robert J, Reya, Tannishtha
• Format: Article
• Language: English
• Subjects: animal models; Animals; Arrestins - genetics; Arrestins - metabolism; beta-Arrestins; Biological Sciences; Blast Crisis - genetics; Blast Crisis - metabolism; Blast Crisis - pathology; Bone marrow; Bone marrow cells; Cancer; carcinogenesis; Cell culture techniques; Chronic myeloid leukemia; Disease models; G-protein coupled receptors; Humans; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Male; Mice; Mice, Knockout; mutants; Mutation; Myeloid leukemia; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; patients; scaffolding proteins; Stem cells; Viral diseases; Wnt Signaling Pathway
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1209815109

β-Arrestins were initially discovered as negative regulators of G protein-coupled receptor signaling. Although β-arrestins have more recently been implicated as scaffold proteins that interact with various mitogenic and developmental signals, the genetic role of β-arrestins in driving oncogenesis is not known. Here we have investigated the role of β-arrestin in hematologic malignancies and have found that although both β-arrestin1 and -2 are expressed in the hematopoietic system, loss of β-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 β-arrestin2 leads to a significant inhibition of β-catenin stabilization, and ectopic activation of Wnt signaling reverses the defects observed in the β-arrestin2 mutant cells. These data cumulatively show that β-arrestin2 is essential for CML disease propagation and indicate that β-arrestins and the Wnt/β-catenin pathway lie in a signaling hierarchy in the context of CML cancer stem cell maintenance.