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: Augusta Di Savino, Cristina Panuzzo, Stefania Rocca, Ubaldo Familiari, Rocco Piazza, Sabrina Crivellaro, Giovanna Carrà, Roberta Ferretti, Federica Fusella, Emilia Giugliano, Annalisa Camporeale, Irene Franco, Barbara Miniscalco, Juan Carlos Cutrin, Emilia Turco, Lorenzo Silengo, Emilio Hirsch, Giovanna Rege-Cambrin, Carlo Gambacorti-Passerini, Pier Paolo Pandolfi, Mauro Papotti, Giuseppe Saglio, Guido Tarone, Alessandro Morotti, Mara Brancaccio
• Journal: Blood (Blood) Vol. 125 Issue 14 Pg. 2245-53 (Apr 02 2015) ISSN: 1528-0020 [Electronic] United States
• PMID: 25678499 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society of Hematology.

Chemical References

• Benzamides
• Carrier Proteins
• Chp-1 protein, mouse
• Molecular Chaperones
• Piperazines
• Protein Kinase Inhibitors
• Pyrimidines
• RNA, Messenger
• Imatinib Mesylate
• Fusion Proteins, bcr-abl
• rho-Associated Kinases

Topics

• Animals
• Apoptosis
• Benzamides (pharmacology)
• Blotting, Western
• Bone Marrow (metabolism, pathology)
• Carrier Proteins (physiology)
• Cell Proliferation
• Drug Resistance, Neoplasm (genetics)
• Flow Cytometry
• Fusion Proteins, bcr-abl (genetics, metabolism)
• Humans
• Imatinib Mesylate
• Immunoenzyme Techniques
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (genetics, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Molecular Chaperones
• Philadelphia Chromosome
• Piperazines (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Pyrimidines (pharmacology)
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Cells, Cultured
• rho-Associated Kinases (antagonists & inhibitors, genetics, metabolism)