title: β-Arrestin2 mediates the initiation and progression of myeloid leukemia.
abstract: 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.
authors: Department of Pharmacology,  University of California, San Diego School of Medicine and Sanford Consortium for Regenerative Medicine, La Jolla, CA 92093.
authors: Mark
authors: M
authors: Fereshteh
authors: Takahiro
authors: T
authors: Ito
authors: Jeffrey J
authors: JJ
authors: Kovacs
authors: Chen
authors: C
authors: Zhao
authors: Hyog Young
authors: HY
authors: Kwon
authors: Valerie
authors: V
authors: Tornini
authors: Takaaki
authors: T
authors: Konuma
authors: Minyong
authors: M
authors: Chen
authors: Robert J
authors: RJ
authors: Lefkowitz
authors: Tannishtha
authors: T
authors: Reya
mesh_terms: D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D001752:Blast Crisis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D060449:Wnt Signaling Pathway; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D009363:Neoplasm Proteins; D000071557:beta-Arrestins