Τίτλος:
Exploiting the role of hypoxia-inducible factor 1 and pseudohypoxia in the myelodysplastic syndrome pathophysiology
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoi-etic 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. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
Συγγραφείς:
Stergiou, I.E.
Kambas, K.
Poulaki, A.
Giannouli, S.
Katsila, T.
Dimitrakopoulou, A.
Vidali, V.
Mouchtouris, V.
Kloukina, I.
Xingi, E.
Pagakis, S.N.
Probert, L.
Patrinos, G.P.
Ritis, K.
Tzioufas, A.G.
Voulgarelis, M.
Περιοδικό:
International Journal of Molecular Sciences
Λέξεις-κλειδιά:
biological marker; CD11b antigen; CD34 antigen; dna damage inducible transcript 4; hypoxia inducible factor 1; hypoxia inducible factor 1alpha; indocyanine green; lysosome associated membrane protein 1; messenger RNA; microtubule associated protein 1a 1b light chain 3b; myeloperoxidase; nitroimidazole derivative; oxygen; regulated in development and dna damage response; translocase of outer mitochondrial membrane 20; unclassified drug; CD34 antigen; DDIT4 protein, human; hypoxia inducible factor 1; nitroimidazole derivative; transcription factor, adult; Article; autophagic cell death; autophagosome; bone marrow; bone marrow biopsy; controlled study; dysplasia; electron microscopy; endoplasmic reticulum; flow cytometry; hematopoietic stem cell; human; human cell; human tissue; immunofluorescence; microscopy; mitochondrion; mitophagy; myelodysplastic syndrome; myeloid progenitor cell; myelopoiesis; pathophysiology; protein expression; protein expression level; protein function; real time polymerase chain reaction; upregulation; aged; autophagy; bone marrow cell; cell differentiation; cell lineage; cell proliferation; drug effect; female; hypoxia; male; metabolism; middle aged; mitophagy; myelodysplastic syndrome; ultrastructure; very elderly, Aged; Aged, 80 and over; Antigens, CD34; Autophagy; Bone Marrow; Cell Differentiation; Cell Lineage; Cell Proliferation; Female; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Male; Middle Aged; Mitophagy; Myelodysplastic Syndromes; Myeloid Cells; Nitroimidazoles; Transcription Factors; Up-Regulation
DOI:
10.3390/ijms22084099
