Exploiting the Role of Hypoxia-Inducible Factor 1 and Pseudohypoxia in the Myelodysplastic Syndrome Pathophysiology

International Journal of Molecular Sciences

StamatisN. Pagakis¹  Ismini Kloukina²  AthanasiosG. Tzioufas³  Michael Voulgarelis³  IoannaE. Stergiou³  Aikaterini Poulaki³  GeorgeP. Patrinos⁴  Konstantinos Ritis⁵  Stavroula Giannouli⁶  Theodora Katsila⁷  Aglaia Dimitrakopoulou⁸  Lesley Probert⁹  Konstantinos Kambas⁹  Vasileios Mouchtouris^1,10  Veroniki Vidali^1,10  Evangelia Xingi^1,11 

[1] Biological Imaging Unit, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece;Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece;Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;Department of Pharmacy, University of Patras, 26504 Patras, Greece;First Department of Internal Medicine, University General Hospital of Alexandroupolis, Democritus University of Thrace, 68100 Alexandroupolis, Greece;Hematology Unit, Second Department of Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece;Laboratory of Flow Cytometry, Immunology Department, Laiko Hospital of Athens, 11526 Athens, Greece;Laboratory of Molecular Genetics, Department of Immunology, Hellenic Pasteur Institute, 11521 Athens, Greece;Laboratory of Synthesis of Natural Products and Bioorganic Chemistry, Institute of Nanoscience and Nanotechnology, National Center for Scientific Research “Demokritos”, 15341 Athens, Greece;Light Microscopy Unit, Hellenic Pasteur Institute, 11521 Athens, Greece;

关键词: myelodysplastic syndromes;    hypoxia-inducible factor 1;    pseudohypoxia;    autophagy;    mitophagy;   

DOI  :  10.3390/ijms22084099

来源: DOAJ

【 摘 要 】

Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic stem (HSCs) and/or progenitor cells disorders. The established dependence of MDS progenitors on the hypoxic bone marrow (BM) microenvironment turned scientific interests to the transcription factor hypoxia-inducible factor 1 (HIF-1). HIF-1 facilitates quiescence maintenance and regulates differentiation by manipulating HSCs metabolism, being thus an appealing research target. Therefore, we examine the aberrant HIF-1 stabilization in BMs from MDS patients and controls (CTRLs). Using a nitroimidazole–indocyanine conjugate, we show that HIF-1 aberrant expression and transcription activity is oxygen independent, establishing the phenomenon of pseudohypoxia in MDS BM. Next, we examine mitochondrial quality and quantity along with levels of autophagy in the differentiating myeloid lineage isolated from fresh BM MDS and CTRL aspirates given that both phenomena are HIF-1 dependent. We show that the mitophagy of abnormal mitochondria and autophagic death are prominently featured in the MDS myeloid lineage, their severity increasing with intra-BM blast counts. Finally, we use in vitro cultured CD34+ HSCs isolated from fresh human BM aspirates to manipulate HIF-1 expression and examine its potential as a therapeutic target. We find that despite being cultured under 21% FiO2, HIF-1 remained aberrantly stable in all MDS cultures. Inhibition of the HIF-1α subunit had a variable beneficial effect in all <5%-intra-BM blasts-MDS, while it had no effect in CTRLs or in ≥5%-intra-BM blasts-MDS that uniformly died within 3 days of culture. We conclude that HIF-1 and pseudohypoxia are prominently featured in MDS pathobiology, and their manipulation has some potential in the therapeutics of benign MDS.

【 授权许可】

Unknown