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

• Published in: International journal of molecular sciences Vol. 22; no. 8; p. 4099
• Main Authors: Stergiou, Ioanna E, Kambas, Konstantinos, Poulaki, Aikaterini, Giannouli, Stavroula, 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
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 15-04-2021; MDPI
• Subjects: Aged; Aged, 80 and over; Antigens, CD34 - metabolism; Autophagy; Autophagy - drug effects; Bone marrow; Bone Marrow - drug effects; Bone Marrow - metabolism; CD34 antigen; Cell culture; Cell Differentiation - drug effects; Cell Lineage; Cell Proliferation - drug effects; Cells (biology); Cloning; Female; Gene expression; Genotype & phenotype; Hematopoietic stem cells; Humans; Hypoxia; Hypoxia - metabolism; Hypoxia - physiopathology; Hypoxia-inducible factor 1; Hypoxia-Inducible Factor 1 - metabolism; Hypoxia-inducible factor 1a; Male; Metabolism; Microenvironments; Middle Aged; Mitochondria; mitophagy; Mitophagy - drug effects; Mutation; Myelodysplastic syndrome; Myelodysplastic syndromes; Myelodysplastic Syndromes - metabolism; Myelodysplastic Syndromes - physiopathology; Myeloid Cells - drug effects; Myeloid Cells - metabolism; Myeloid Cells - ultrastructure; Nitroimidazole; Nitroimidazoles - pharmacology; Osteoprogenitor cells; Pathophysiology; Phagocytosis; Progenitor cells; Protein expression; Proteins; pseudohypoxia; Therapeutic targets; Transcription Factors - metabolism; Up-Regulation - drug effects; hypoxia-inducible factor 1; pseudohypoxia; mitophagy; autophagy; myelodysplastic syndromes
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22084099

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.