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Morgana acts as an oncosuppressor in chronic myeloid leukemia
Augusta Di Savino1, Cristina Panuzzo2, Stefania Rocca1
1Department of Molecular Biotechnology and Health Sciences, and.
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.
Insights
Morgana protein loss causes myeloproliferative disease and leukemia by disrupting genomic stability. Underexpression of morgana in CML patients predicts poor imatinib response, but ROCK inhibitors may restore treatment efficacy.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- Morgana is a protein crucial for regulating centrosome duplication and maintaining genomic stability.
- ROCK signaling is implicated in various cellular processes, including cell proliferation and survival.
Purpose of the Study:
- To investigate the role of morgana in myeloproliferative diseases and its impact on chronic myeloid leukemia (CML).
- To explore the therapeutic potential of targeting ROCK signaling in CML patients with morgana underexpression.
Main Methods:
- Analysis of morgana (+/-) mice developing myeloproliferative disease.
- Examination of morgana expression levels in bone marrow samples from patients with atypical CML and Philadelphia-positive CML.
- Assessment of imatinib response in relation to morgana expression and the effect of ROCK inhibitors.
Main Results:
- Morgana deficiency in mice leads to myeloproliferative disease with features of atypical CML, characterized by ROCK hyperactivation, centrosome amplification, and chromosomal abnormalities.
- Morgana is underexpressed in atypical CML and Philadelphia-positive CML patient bone marrow.
- Lower morgana levels in Philadelphia-positive CML correlate with a poorer response to imatinib and suggest synergy with BCR-ABL signaling.
- ROCK inhibition restores imatinib-induced apoptosis in morgana-underexpressing CML models.
Conclusions:
- Morgana functions as an oncosuppressor, and its loss contributes to leukemia development and progression.
- Morgana underexpression negatively impacts imatinib efficacy in Philadelphia-positive CML.
- Combined treatment with imatinib and ROCK inhibitors presents a potential strategy to overcome resistance in patients with low morgana levels.
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