Decrease in α-Globin and Increase in the Autophagy-Activating Kinase ULK1 mRNA in Erythroid Precursors from β-Thalassemia Patients Treated with Sirolimus
The β-thalassemias are hereditary monogenic diseases characterized by a low or absent production of adult hemoglobin and excess in the content of α-globin. This excess is cytotoxic for the erythroid cells and responsible for the β-thalassemia-associated ineffective erythropoiesis. Therefore, the dec...
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MDPI AG
2023-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/20/15049 |
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| author | Matteo Zurlo Cristina Zuccato Lucia Carmela Cosenza Jessica Gasparello Maria Rita Gamberini Alice Stievano Monica Fortini Marco Prosdocimi Alessia Finotti Roberto Gambari |
| author_facet | Matteo Zurlo Cristina Zuccato Lucia Carmela Cosenza Jessica Gasparello Maria Rita Gamberini Alice Stievano Monica Fortini Marco Prosdocimi Alessia Finotti Roberto Gambari |
| author_sort | Matteo Zurlo |
| collection | DOAJ |
| description | The β-thalassemias are hereditary monogenic diseases characterized by a low or absent production of adult hemoglobin and excess in the content of α-globin. This excess is cytotoxic for the erythroid cells and responsible for the β-thalassemia-associated ineffective erythropoiesis. Therefore, the decrease in excess α-globin is a relevant clinical effect for these patients and can be realized through the induction of fetal hemoglobin, autophagy, or both. The in vivo effects of sirolimus (rapamycin) and analogs on the induction of fetal hemoglobin (HbF) are of key importance for therapeutic protocols in a variety of hemoglobinopathies, including β-thalassemias. In this research communication, we report data showing that a decrease in autophagy-associated p62 protein, increased expression of ULK-1, and reduction in excess α-globin are occurring in erythroid precursors (ErPCs) stimulated in vitro with low dosages of sirolimus. In addition, increased ULK-1 mRNA content and a decrease in α-globin content were found in ErPCs isolated from β-thalassemia patients recruited for the NCT03877809 clinical trial and treated with 0.5–2 mg/day sirolimus. Our data support the concept that autophagy, ULK1 expression, and α-globin chain reduction should be considered important endpoints in sirolimus-based clinical trials for β-thalassemias. |
| first_indexed | 2024-03-10T21:13:04Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T21:13:04Z |
| publishDate | 2023-10-01 |
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| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-c0382c4011cb481eba8fab3644c2458e2023-11-19T16:40:54ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-10-0124201504910.3390/ijms242015049Decrease in α-Globin and Increase in the Autophagy-Activating Kinase ULK1 mRNA in Erythroid Precursors from β-Thalassemia Patients Treated with SirolimusMatteo Zurlo0Cristina Zuccato1Lucia Carmela Cosenza2Jessica Gasparello3Maria Rita Gamberini4Alice Stievano5Monica Fortini6Marco Prosdocimi7Alessia Finotti8Roberto Gambari9Department of Life Sciences and Biotechnology, Ferrara University, 44121 Ferrara, ItalyDepartment of Life Sciences and Biotechnology, Ferrara University, 44121 Ferrara, ItalyDepartment of Life Sciences and Biotechnology, Ferrara University, 44121 Ferrara, ItalyDepartment of Life Sciences and Biotechnology, Ferrara University, 44121 Ferrara, ItalyThalassemia Unit, Arcispedale S. Anna, 44121 Ferrara, ItalyThalassemia Unit, Arcispedale S. Anna, 44121 Ferrara, ItalyThalassemia Unit, Arcispedale S. Anna, 44121 Ferrara, ItalyRare Partners S.r.L. Impresa Sociale, 20123 Milano, ItalyDepartment of Life Sciences and Biotechnology, Ferrara University, 44121 Ferrara, ItalyDepartment of Life Sciences and Biotechnology, Ferrara University, 44121 Ferrara, ItalyThe β-thalassemias are hereditary monogenic diseases characterized by a low or absent production of adult hemoglobin and excess in the content of α-globin. This excess is cytotoxic for the erythroid cells and responsible for the β-thalassemia-associated ineffective erythropoiesis. Therefore, the decrease in excess α-globin is a relevant clinical effect for these patients and can be realized through the induction of fetal hemoglobin, autophagy, or both. The in vivo effects of sirolimus (rapamycin) and analogs on the induction of fetal hemoglobin (HbF) are of key importance for therapeutic protocols in a variety of hemoglobinopathies, including β-thalassemias. In this research communication, we report data showing that a decrease in autophagy-associated p62 protein, increased expression of ULK-1, and reduction in excess α-globin are occurring in erythroid precursors (ErPCs) stimulated in vitro with low dosages of sirolimus. In addition, increased ULK-1 mRNA content and a decrease in α-globin content were found in ErPCs isolated from β-thalassemia patients recruited for the NCT03877809 clinical trial and treated with 0.5–2 mg/day sirolimus. Our data support the concept that autophagy, ULK1 expression, and α-globin chain reduction should be considered important endpoints in sirolimus-based clinical trials for β-thalassemias.https://www.mdpi.com/1422-0067/24/20/15049β-thalassemiaautophagyfetal hemoglobinα-globinrapamycinsirolimus |
| spellingShingle | Matteo Zurlo Cristina Zuccato Lucia Carmela Cosenza Jessica Gasparello Maria Rita Gamberini Alice Stievano Monica Fortini Marco Prosdocimi Alessia Finotti Roberto Gambari Decrease in α-Globin and Increase in the Autophagy-Activating Kinase ULK1 mRNA in Erythroid Precursors from β-Thalassemia Patients Treated with Sirolimus International Journal of Molecular Sciences β-thalassemia autophagy fetal hemoglobin α-globin rapamycin sirolimus |
| title | Decrease in α-Globin and Increase in the Autophagy-Activating Kinase ULK1 mRNA in Erythroid Precursors from β-Thalassemia Patients Treated with Sirolimus |
| title_full | Decrease in α-Globin and Increase in the Autophagy-Activating Kinase ULK1 mRNA in Erythroid Precursors from β-Thalassemia Patients Treated with Sirolimus |
| title_fullStr | Decrease in α-Globin and Increase in the Autophagy-Activating Kinase ULK1 mRNA in Erythroid Precursors from β-Thalassemia Patients Treated with Sirolimus |
| title_full_unstemmed | Decrease in α-Globin and Increase in the Autophagy-Activating Kinase ULK1 mRNA in Erythroid Precursors from β-Thalassemia Patients Treated with Sirolimus |
| title_short | Decrease in α-Globin and Increase in the Autophagy-Activating Kinase ULK1 mRNA in Erythroid Precursors from β-Thalassemia Patients Treated with Sirolimus |
| title_sort | decrease in α globin and increase in the autophagy activating kinase ulk1 mrna in erythroid precursors from β thalassemia patients treated with sirolimus |
| topic | β-thalassemia autophagy fetal hemoglobin α-globin rapamycin sirolimus |
| url | https://www.mdpi.com/1422-0067/24/20/15049 |
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