Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	Exploiting the role of hypoxia-inducible factor 1 and pseudohypoxia in the myelodysplastic syndrome pathophysiology
Δημιουργός/Συγγραφέας:	Stergiou, Ioanna E Kambas, Konstantinos Poulaki, Aikaterini Giannouli, Stavroula [EL] Κατσίλα, Θεοδώρα[EN] Katsila, Theodora Dimitrakopoulou, Aglaia Vidali, Veroniki Mouchtouris, Vasileios Kloukina, Ismini Xingi, Evangelia Pagakis, Stamatis N Probert, Lesley Patrinos, George P Ritis, Konstantinos Tzioufas, Athanasios G Voulgarelis, Michael
Εκδότης:	MDPI
Ημερομηνία:	2021-04-15
Γλώσσα:	Αγγλικά
ISSN:	1422-0067
DOI:	10.3390/ijms22084099
Άλλο:	33921064
Περίληψη:	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.
Τίτλος πηγής δημοσίευσης:	International journal of molecular sciences Special Issue: Metabolic Disturbances in Hematologic Malignancies
Τόμος/Κεφάλαιο:	22
Τεύχος:	8
Σελίδες:	4099
Θεματική Κατηγορία:	[EL] Χημική Βιολογία[EN] Chemical Biology [EL] Κυτταρολογία[EN] Cytology [EL] Βιοχημεία[EN] Biochemistry [EL] Νεοπλάσματα. Όγκοι. Ογκολογία (περ. Καρκίνος, κακινογόνες ουσίες)[EN] Neoplasms. Tumors. Oncology (Incl.cancer, carcinogens)
Λέξεις-Κλειδιά:	Autophagy Hypoxia-inducible factor 1 Mitophagy Myelodysplastic syndrome Pseudohypoxia Aged Aged, 80 and over Antigens, CD34 Bone Marrow Cell Differentiation Cell Lineage Cell Proliferation Female Humans Hypoxia Hypoxia-Inducible Factor 1 Male Middle Aged Myelodysplastic Syndromes Myeloid Cells Nitroimidazoles Transcription Factors Up-Regulation
Κάτοχος πνευματικών δικαιωμάτων:	Copyright © 2021 by the Authors. Licensee MDPI, Basel, Switzerland
Ηλεκτρονική διεύθυνση στον εκδότη (link):	https://www.mdpi.com/1422-0067/22/8/4099
Ηλεκτρονική διεύθυνση περιοδικού (link) :	https://www.mdpi.com/journal/ijms
Εμφανίζεται στις συλλογές:	Ινστιτούτο Χημικής Βιολογίας - Επιστημονικό έργο