Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Decrease of α-Globin and Increase of the Autophagy-Activating Kinase ULK1 mRNA in Erythroid Precursors from β-Thalassemia Patients Treated with Sirolimus

Matteo Zurlo
ORCID logo ,
Cristina Zuccato
,
Lucia Carmela Cosenza
,
Jessica Gasparello
,
Maria Rita Gamberini
,
Alice Stievano
,
Monica Fortini
,
Marco Prosdocimi
ORCID logo ,
Alessia Finotti
* ORCID logo ,
Roberto Gambari
*
Version 1 : Received: 1 September 2023 / Approved: 4 September 2023 / Online: 4 September 2023 (10:43:35 CEST)

A peer-reviewed article of this Preprint also exists.

Zurlo, M.; Zuccato, C.; Cosenza, L.C.; Gasparello, J.; Gamberini, M.R.; Stievano, A.; Fortini, M.; Prosdocimi, M.; Finotti, A.; Gambari, R. Decrease in α-Globin and Increase in the Autophagy-Activating Kinase ULK1 mRNA in Erythroid Precursors from β-Thalassemia Patients Treated with Sirolimus. Int. J. Mol. Sci. 2023, 24, 15049. Zurlo, M.; Zuccato, C.; Cosenza, L.C.; Gasparello, J.; Gamberini, M.R.; Stievano, A.; Fortini, M.; Prosdocimi, M.; Finotti, A.; Gambari, R. Decrease in α-Globin and Increase in the Autophagy-Activating Kinase ULK1 mRNA in Erythroid Precursors from β-Thalassemia Patients Treated with Sirolimus. Int. J. Mol. Sci. 2023, 24, 15049.

Abstract

The β-thalassemias are hereditary monogenic diseases characterized by 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 of the β-thalassemia associated ineffective erythropoiesis. Therefore, the decrease of α-globin excess is a relevant clinical effect for these patients and can be obtained by induction of fetal hemoglobin, by autophagy, or both. The in vivo effects of sirolimus (rapamycin) and analogues on induction of fetal hemoglobin (HbF) is of key importance for therapeutic protocols in a variety of hemoglobinopathies, including β-thalassemia. In this research communication, we report data showing that decrease of autophagy-associated p62 protein, increased expression of ULK-1 and reduction of the excess of α-globin is operating in erythroid precursors (ErPCs) stimulated in vitro with low dosages of sirolimus. In addition, increased ULK-1 mRNA content and decrease of 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-thalassemia.

Keywords

β-thalassemia; autophagy; fetal hemoglobin; α-globin; rapamycin; sirolimus; ULK1

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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