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

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2023 Oct 28

PMID 37894732

Authors

Matteo Zurlo

Cristina Zuccato

Lucia Carmela Cosenza

Jessica Gasparello

Maria Rita Gamberini

Alice Stievano

Monica Fortini

Marco Prosdocimi

Alessia Finotti

Roberto Gambari

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Genetic Modifiers of Hemoglobin Expression from a Clinical Perspective in Hemoglobinopathy Patients with Beta Thalassemia and Sickle Cell Disease.

Diamantidis M, Ikonomou G, Argyrakouli I, Pantelidou D, Delicou S Int J Mol Sci. 2024; 25(22).

PMID: 39595957 PMC: 11593634. DOI: 10.3390/ijms252211886.

Therapeutic Relevance of Inducing Autophagy in β-Thalassemia.

Gambari R, Finotti A Cells. 2024; 13(11.

PMID: 38891049 PMC: 11171814. DOI: 10.3390/cells13110918.

Increased Expression of α-Hemoglobin Stabilizing Protein (AHSP) mRNA in Erythroid Precursor Cells Isolated from β-Thalassemia Patients Treated with Sirolimus (Rapamycin).

Zurlo M, Zuccato C, Cosenza L, Gamberini M, Finotti A, Gambari R J Clin Med. 2024; 13(9).

PMID: 38731008 PMC: 11084795. DOI: 10.3390/jcm13092479.

Impact of α-Globin Gene Expression and α-Globin Modifiers on the Phenotype of β-Thalassemia and Other Hemoglobinopathies: Implications for Patient Management.

Traeger-Synodinos J, Vrettou C, Sofocleous C, Zurlo M, Finotti A, Gambari R Int J Mol Sci. 2024; 25(6).

PMID: 38542374 PMC: 10969871. DOI: 10.3390/ijms25063400.

References

Weatherall D . Phenotype-genotype relationships in monogenic disease: lessons from the thalassaemias. Nat Rev Genet. 2001; 2(4):245-55. DOI: 10.1038/35066048. View

Pallet N, Fernandez-Ramos A, Loriot M . Impact of Immunosuppressive Drugs on the Metabolism of T Cells. Int Rev Cell Mol Biol. 2018; 341:169-200. DOI: 10.1016/bs.ircmb.2018.05.009. View

Origa R . β-Thalassemia. Genet Med. 2016; 19(6):609-619. DOI: 10.1038/gim.2016.173. View

Anastasiadi A, Tzounakas V, Dzieciatkowska M, Arvaniti V, Papageorgiou E, Papassideri I . Innate Variability in Physiological and Omics Aspects of the Beta Thalassemia Trait-Specific Donor Variation Effects. Front Physiol. 2022; 13:907444. PMC: 9214579. DOI: 10.3389/fphys.2022.907444. View

Rostamzadeh D, Yousefi M, Haghshenas M, Ahmadi M, Dolati S, Babaloo Z . mTOR Signaling pathway as a master regulator of memory CD8 T-cells, Th17, and NK cells development and their functional properties. J Cell Physiol. 2019; 234(8):12353-12368. DOI: 10.1002/jcp.28042. View

Cosenza L, Zuccato C, Zurlo M, Gambari R, Finotti A . Co-Treatment of Erythroid Cells from β-Thalassemia Patients with CRISPR-Cas9-Based β39-Globin Gene Editing and Induction of Fetal Hemoglobin. Genes (Basel). 2022; 13(10). PMC: 9601852. DOI: 10.3390/genes13101727. View

Osmulski P, Gaczynska M . Rapamycin allosterically inhibits the proteasome. Mol Pharmacol. 2013; 84(1):104-13. DOI: 10.1124/mol.112.083873. View

Mettananda S, Gibbons R, Higgs D . α-Globin as a molecular target in the treatment of β-thalassemia. Blood. 2015; 125(24):3694-701. PMC: 4497969. DOI: 10.1182/blood-2015-03-633594. View

Zurlo M, Gasparello J, Cosenza L, Breveglieri G, Papi C, Zuccato C . Production and Characterization of K562 Cellular Clones Hyper-Expressing the Gene Encoding α-Globin: Preliminary Analysis of Biomarkers Associated with Autophagy. Genes (Basel). 2023; 14(3). PMC: 10048432. DOI: 10.3390/genes14030556. View

10.

Shin W, Park J, Chung K . The central regulator p62 between ubiquitin proteasome system and autophagy and its role in the mitophagy and Parkinson's disease. BMB Rep. 2019; 53(1):56-63. PMC: 6999829. View

11.

Zhao J, Zhai B, Gygi S, Goldberg A . mTOR inhibition activates overall protein degradation by the ubiquitin proteasome system as well as by autophagy. Proc Natl Acad Sci U S A. 2015; 112(52):15790-7. PMC: 4703015. DOI: 10.1073/pnas.1521919112. View

12.

Cosenza L, Gasparello J, Romanini N, Zurlo M, Zuccato C, Gambari R . Efficient CRISPR-Cas9-based genome editing of β-globin gene on erythroid cells from homozygous β39-thalassemia patients. Mol Ther Methods Clin Dev. 2021; 21:507-523. PMC: 8091488. DOI: 10.1016/j.omtm.2021.03.025. View

13.

Byun S, Lee E, Lee K . Therapeutic Implications of Autophagy Inducers in Immunological Disorders, Infection, and Cancer. Int J Mol Sci. 2017; 18(9). PMC: 5618608. DOI: 10.3390/ijms18091959. View

14.

Cosenza L, Breda L, Breveglieri G, Zuccato C, Finotti A, Lampronti I . A validated cellular biobank for β-thalassemia. J Transl Med. 2016; 14:255. PMC: 5010737. DOI: 10.1186/s12967-016-1016-4. View

15.

Anastasiadi A, Tzounakas V, Arvaniti V, Dzieciatkowska M, Stamoulis K, Lekka M . Red Blood Cell Proteasome in Beta-Thalassemia Trait: Topology of Activity and Networking in Blood Bank Conditions. Membranes (Basel). 2021; 11(9). PMC: 8466122. DOI: 10.3390/membranes11090716. View

16.

Khaibullina A, Almeida L, Wang L, Kamimura S, Wong E, Nouraie M . Rapamycin increases fetal hemoglobin and ameliorates the nociception phenotype in sickle cell mice. Blood Cells Mol Dis. 2015; 55(4):363-72. DOI: 10.1016/j.bcmd.2015.08.001. View

17.

Lechauve C, Keith J, Khandros E, Fowler S, Mayberry K, Freiwan A . The autophagy-activating kinase ULK1 mediates clearance of free α-globin in β-thalassemia. Sci Transl Med. 2019; 11(506). PMC: 7441525. DOI: 10.1126/scitranslmed.aav4881. View

18.

Zurlo M, Nicoli F, Proietto D, Dallan B, Zuccato C, Cosenza L . Effects of Sirolimus treatment on patients with β-Thalassemia: Lymphocyte immunophenotype and biological activity of memory CD4 and CD8 T cells. J Cell Mol Med. 2023; 27(3):353-364. PMC: 9889681. DOI: 10.1111/jcmm.17655. View

19.

Zuccato C, Cosenza L, Zurlo M, Lampronti I, Borgatti M, Scapoli C . Treatment of Erythroid Precursor Cells from β-Thalassemia Patients with Alkaloids: Induction of Fetal Hemoglobin Production. Int J Mol Sci. 2021; 22(24). PMC: 8706579. DOI: 10.3390/ijms222413433. View

20.

Gaudre N, Cougoul P, Bartolucci P, Dorr G, Bura-Riviere A, Kamar N . Improved Fetal Hemoglobin With mTOR Inhibitor-Based Immunosuppression in a Kidney Transplant Recipient With Sickle Cell Disease. Am J Transplant. 2017; 17(8):2212-2214. DOI: 10.1111/ajt.14263. View