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 non-recurrent 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 Ph+ CML standard treatment. Thus, Morgana acts as an oncosuppressor with different modalities: on one hand, Morgana underexpression induces centrosome amplification and cytogenetic abnormalities, on the other, 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, in combination with Imatinib treatment, can overcome suboptimal responses in patients in which Morgana is underexpressed.
MORGANA/CHP1 ACTS AS AN ONCOSUPPRESSOR IN CHRONIC MYELOID LEUKEMIA
DI SAVINO, AUGUSTA;PANUZZO, Cristina;CRIVELLARO, SABRINA;MINISCALCO, Barbara;CUTRIN, Juan Carlos;TURCO, Emilia;HIRSCH, Emilio;Pandolfi PP;PAPOTTI, Mauro Giulio;SAGLIO, Giuseppe;MOROTTI, Alessandro;BRANCACCIO, Mara
2014-01-01
Abstract
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 non-recurrent 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 Ph+ CML standard treatment. Thus, Morgana acts as an oncosuppressor with different modalities: on one hand, Morgana underexpression induces centrosome amplification and cytogenetic abnormalities, on the other, 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, in combination with Imatinib treatment, can overcome suboptimal responses in patients in which Morgana is underexpressed.
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