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

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