Hypoxia-inducible transcription factors have been identified as regulators of adaptive responses to hypoxia. Over the past 20 years, more than 8000 papers have described their increasingly complex role and regulation in cancer. Presently, it is recognized that hypoxia-inducible factors (HIFs) are regulated by oxygen-dependent and oxygen-independent mechanisms in cancer development; the list of their targets has increased to include more than 500 genes involved in most hallmarks of cancer. Areas covered: Most literature describes the function of HIF factors in solid tumors; however, in the past 10 years, evidence has steadily accumulated to indicate that HIFs are implicated in hematological malignancies. This review summarizes our current understanding of the function and regulation of HIF factors in hematopoiesis and leukemia. Moreover, we provide an update on pharmacological inhibitors of this pathway that have shown promising therapeutic effects in clinical trials or leukemia pre-clinical models. Expert opinion: The inhibition of the function of HIF factors may provide an interesting approach for treating leukemia. We posit that before moving into the clinic, we should (i) fully characterize the outcome of HIF inhibition in specific leukemia contexts (ii) test the possibility of combining HIF-targeting strategies with cytotoxic compounds and (iii) consider patient selection to increase therapeutic efficacy.
Keywords: HIF; HIF inhibitors; hematopoiesis; hematopoietic stem cells (HSCs); hypoxia; leukemia; leukemia stem cells (LSCs).