title: Morgana acts as an oncosuppressor in chronic myeloid leukemia.
abstract: We recently described morgana as an essential protein able to regulate centrosome duplication and genomic stability, by inhibiting ROCK. Here we show that morgana (+/-) mice spontaneously develop a lethal myeloproliferative disease resembling human atypical chronic myeloid leukemia (aCML), preceded by ROCK hyperactivation, centrosome amplification, and cytogenetic abnormalities in the bone marrow (BM). Moreover, we found that morgana is underexpressed in the BM of patients affected by atypical CML, a disorder of poorly understood molecular basis, characterized by nonrecurrent cytogenetic abnormalities. Morgana is also underexpressed in the BM of a portion of patients affected by Philadelphia-positive CML (Ph(+) CML) caused by the BCR-ABL oncogene, and in this condition, morgana underexpression predicts a worse response to imatinib, the standard treatment for Ph(+) CML. Thus, morgana acts as an oncosuppressor with different modalities: (1) Morgana underexpression induces centrosome amplification and cytogenetic abnormalities, and (2) in Ph(+) CML, it synergizes with BCR-ABL signaling, reducing the efficacy of imatinib treatment. Importantly, ROCK inhibition in the BM of patients underexpressing morgana restored the efficacy of imatinib to induce apoptosis, suggesting that ROCK inhibitors, combined with imatinib treatment, can overcome suboptimal responses in patients in which morgana is underexpressed.
authors: Department of Molecular Biotechnology and Health Sciences, and.
authors: Augusta
authors: A
authors: Di Savino
authors: Division of Internal Medicine and Hematology, Department of Clinical and Biological Sciences, University of Torino, Torino, Italy;
authors: Cristina
authors: C
authors: Panuzzo
authors: Department of Molecular Biotechnology and Health Sciences, and.
authors: Stefania
authors: S
authors: Rocca
authors: Division of Pathology, Department of Oncology, University of Torino at St Luigi Hospital, Torino, Italy;
authors: Ubaldo
authors: U
authors: Familiari
authors: Department of Health Sciences, University of Milano-Bicocca, Monza, Italy;
authors: Rocco
authors: R
authors: Piazza
authors: Division of Internal Medicine and Hematology, Department of Clinical and Biological Sciences, University of Torino, Torino, Italy;
authors: Sabrina
authors: S
authors: Crivellaro
authors: Division of Internal Medicine and Hematology, Department of Clinical and Biological Sciences, University of Torino, Torino, Italy;
authors: Giovanna
authors: G
authors: Carrà
authors: Department of Molecular Biotechnology and Health Sciences, and.
authors: Roberta
authors: R
authors: Ferretti
authors: Department of Molecular Biotechnology and Health Sciences, and.
authors: Federica
authors: F
authors: Fusella
authors: Division of Internal Medicine and Hematology, Department of Clinical and Biological Sciences, University of Torino, Torino, Italy;
authors: Emilia
authors: E
authors: Giugliano
authors: Department of Molecular Biotechnology and Health Sciences, and.
authors: Annalisa
authors: A
authors: Camporeale
authors: Department of Molecular Biotechnology and Health Sciences, and.
authors: Irene
authors: I
authors: Franco
authors: Department of Veterinary Sciences, Clinical Section, Grugliasco, Italy; and.
authors: Barbara
authors: B
authors: Miniscalco
authors: Department of Molecular Biotechnology and Health Sciences, and.
authors: Juan Carlos
authors: JC
authors: Cutrin
authors: Department of Molecular Biotechnology and Health Sciences, and.
authors: Emilia
authors: E
authors: Turco
authors: Department of Molecular Biotechnology and Health Sciences, and.
authors: Lorenzo
authors: L
authors: Silengo
authors: Department of Molecular Biotechnology and Health Sciences, and.
authors: Emilio
authors: E
authors: Hirsch
authors: Division of Internal Medicine and Hematology, Department of Clinical and Biological Sciences, University of Torino, Torino, Italy;
authors: Giovanna
authors: G
authors: Rege-Cambrin
authors: Department of Health Sciences, University of Milano-Bicocca, Monza, Italy;
authors: Carlo
authors: C
authors: Gambacorti-Passerini
authors: Department of Molecular Biotechnology and Health Sciences, and Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors: Pier Paolo
authors: PP
authors: Pandolfi
authors: Division of Pathology, Department of Oncology, University of Torino at St Luigi Hospital, Torino, Italy;
authors: Mauro
authors: M
authors: Papotti
authors: Division of Internal Medicine and Hematology, Department of Clinical and Biological Sciences, University of Torino, Torino, Italy;
authors: Giuseppe
authors: G
authors: Saglio
authors: Department of Molecular Biotechnology and Health Sciences, and.
authors: Guido
authors: G
authors: Tarone
authors: Division of Internal Medicine and Hematology, Department of Clinical and Biological Sciences, University of Torino, Torino, Italy;
authors: Alessandro
authors: A
authors: Morotti
authors: Department of Molecular Biotechnology and Health Sciences, and.
authors: Mara
authors: M
authors: Brancaccio
mesh_terms: D000818:Animals; D017209:Apoptosis; D001549:Benzamides / Q000494:pharmacology*; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000502:physiology*; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D007124:Immunoenzyme Techniques; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018832:Molecular Chaperones; D010677:Philadelphia Chromosome; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D001549:Benzamides; D002352:Carrier Proteins; C478383:Chp-1 protein, mouse; D018832:Molecular Chaperones; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D054460:rho-Associated Kinases