title: Redundant and nonredundant roles for Cdc42 and Rac1 in lymphomas developed in NPM-ALK transgenic mice.
abstract: Increasing evidence suggests that Rho family GTPases could have a critical role in the biology of T-cell lymphoma. In ALK-rearranged anaplastic large cell lymphoma (ALCL), a specific subtype of T-cell lymphoma, the Rho family GTPases Cdc42 and Rac1 are activated by the ALK oncogenic activity. In vitro studies have shown that Cdc42 and Rac1 control rather similar phenotypes of ALCL biology such as the proliferation, survival, and migration of lymphoma cells. However, their role and possible redundancy in ALK-driven lymphoma development in vivo are still undetermined. We genetically deleted Cdc42 or Rac1 in a mouse model of ALK-rearranged ALCL to show that either Cdc42 or Rac1 deletion impaired lymphoma development, modified lymphoma morphology, actin filament distribution, and migration properties of lymphoma cells. Cdc42 or Rac1 deletion primarily affected survival rather than proliferation of lymphoma cells. Apoptosis of lymphoma cells was equally induced following Cdc42 or Rac1 deletion, was associated with upregulation of the proapoptotic molecule Bid, and was blocked by Bcl2 overexpression. Remarkably, Cdc42/Rac1 double deletion, but not Cdc42 or Rac1 single deletions, completely prevented NPM-ALK lymphoma dissemination in vivo. Thus, Cdc42 and Rac1 have nonredundant roles in controlling ALK-rearranged lymphoma survival and morphology but are redundant for lymphoma dissemination, suggesting that targeting both GTPases could represent a preferable therapeutic option for ALCL treatment.
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy; Center for Experimental Medicine and Clinical Studies, University of Torino, Torino, Italy;
authors.forename: Ramesh
authors.initials: R
authors.lastname: Choudhari
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy; Center for Experimental Medicine and Clinical Studies, University of Torino, Torino, Italy;
authors.forename: Valerio Giacomo
authors.initials: VG
authors.lastname: Minero
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy; Center for Experimental Medicine and Clinical Studies, University of Torino, Torino, Italy;
authors.forename: Matteo
authors.initials: M
authors.lastname: Menotti
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy; Center for Experimental Medicine and Clinical Studies, University of Torino, Torino, Italy;
authors.forename: Roberta
authors.initials: R
authors.lastname: Pulito
authors.affiliation: Biotech Research and Innovation Centre, Biomedical Institute, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Cord
authors.initials: C
authors.lastname: Brakebusch
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy; Center for Experimental Medicine and Clinical Studies, University of Torino, Torino, Italy; Department of Pathology, Boston Children's Hospital, Boston, MA; and.
authors.forename: Mara
authors.initials: M
authors.lastname: Compagno
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy; Center for Experimental Medicine and Clinical Studies, University of Torino, Torino, Italy;
authors.forename: Claudia
authors.initials: C
authors.lastname: Voena
authors.affiliation: Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain;
authors.forename: Chiara
authors.identifier: http://orcid.org/0000-0003-4122-701X
authors.initials: C
authors.lastname: Ambrogio
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy; Center for Experimental Medicine and Clinical Studies, University of Torino, Torino, Italy; Department of Pathology, Boston Children's Hospital, Boston, MA; and Harvard Medical School, Boston, MA.
authors.forename: Roberto
authors.identifier: http://orcid.org/0000-0003-1564-8531
authors.initials: R
authors.lastname: Chiarle
mesh_terms: D000818:Animals; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics; D017353:Gene Deletion; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; C581598:Cdc42 protein, mouse; D009479:Neuropeptides; D015514:Oncogene Proteins, Fusion; C484602:Rac1 protein, mouse; C107023:p80(NPM-ALK) protein; D011505:Protein-Tyrosine Kinases; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein