Effect of hypoxia-inducible factors in normal and leukemic stem cell regulation and their potential therapeutic impact

ABSTRACT

Introduction: Hypoxia inducible factors (HIF-1α and HIF-2α) are the main mediators of hypoxic responses that operate in both normal and pathological conditions. Recent evidence indicates that HIF-1α and HIF-2α could have overlapping, unique and even sometimes opposing activities in both normal physiology and disease. Despite an increase in our understanding of the different pathways regulated by HIF-1α and HIF-2α, the role played by each factor in HSC maintenance and leukemogenesis is still controversial.

Areas covered: This review summarizes our current understanding of HIF-1α and HIF-2α activities and discusses the implications and challenges of using HIF inhibitors therapeutically in blood malignancies.

Expert opinion: As HIF inhibitors are currently under clinical evaluation in different cancers, including hematological malignancies, a more thorough understanding of the unique roles performed by HIF-1α and HIF-2α in human neoplasia is warranted.

KEYWORDS:

• Hypoxia
• HIFs
• Leukemia
• Stem cell

Article highlights

• Hypoxia represents an important constituent of the bone marrow (BM) niche.

• The role played by hypoxia-inducible factors (HIFs) in hematopoietic stem cell maintenance and leukemogenesis is controversial at present.

• The role of HIFs subunits on leukemic and normal hematopoietic cells should integrate the effect on the BM niche.

• The spatiotemporal role of HIF-1α and HIF-2α in hematological malignancies needs to be clearly delineated.

• Targeting HIFs required further dissection of the role of each HIF subunit in the context of genetic makeup of the malignant clone(s).

This box summarizes key points contained in the article.

Acknowledgement

We would like to thanks Dr Katie Foster for editing the paper.

Declaration of interest

This review was supported by the Francis Crick Institute core funds to D Bonnet. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. The authors have no conflict of interest to declare.