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miR-15a targets the HSP90 co-chaperone Morgana in chronic myeloid leukemia
Pietro Poggio1, Stefania Rocca1, Federica Fusella1
1Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
Abstract:
Morgana is a ubiquitous HSP90 co-chaperone protein coded by the CHORDC1 gene. Morgana heterozygous mice develop with age a myeloid malignancy resembling human atypical myeloid leukemia (aCML), now renamed MDS/MPN with neutrophilia. Patients affected by this pathology exhibit low Morgana levels in the bone marrow (BM), suggesting that Morgana downregulation plays a causative role in the human malignancy. A decrease in Morgana expression levels is also evident in the BM of a subgroup of Philadelphia-positive (Ph+) chronic myeloid leukemia (CML) patients showing resistance or an incomplete response to imatinib. Despite the relevance of these data, the mechanism through which Morgana expression is downregulated in patients' bone marrow remains unclear. In this study, we investigated the possibility that Morgana expression is regulated by miRNAs and we demonstrated that Morgana is under the control of four miRNAs (miR-15a/b and miR-26a/b) and that miR-15a may account for Morgana downregulation in CML patients.
Insights
Morgana protein downregulation is linked to myeloid malignancies. This study identifies specific microRNAs (miRNAs) that regulate Morgana, with miR-15a potentially causing its decrease in chronic myeloid leukemia patients.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- Morgana (CHORDC1) is an HSP90 co-chaperone.
- Morgana deficiency in mice causes myeloid malignancy (MDS/MPN with neutrophilia).
- Low Morgana levels are observed in myeloid malignancy patients, including imatinib-resistant chronic myeloid leukemia (CML).
Purpose of the Study:
- Investigate the mechanism of Morgana downregulation in bone marrow.
- Determine if microRNAs (miRNAs) regulate Morgana expression.
- Identify specific miRNAs targeting Morgana.
Main Methods:
- Bioinformatic analysis to predict miRNA targets.
- In vitro validation experiments (e.g., luciferase assays, Western blotting).
- Analysis of miRNA and Morgana expression in patient samples.
Main Results:
- Morgana expression is regulated by four miRNAs: miR-15a, miR-15b, miR-26a, and miR-26b.
- miR-15a was identified as a key regulator potentially responsible for Morgana downregulation in CML patients.
- Experimental data confirmed the direct targeting of Morgana by these miRNAs.
Conclusions:
- MicroRNAs play a significant role in regulating Morgana expression.
- miR-15a is implicated in the pathogenesis of chronic myeloid leukemia by downregulating Morgana.
- Targeting these miRNA-Morgana interactions could offer therapeutic strategies for myeloid malignancies.
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