Scientists have discovered a protein, known as HIF-2alpha, that is essential to the activity of haematopoetic stem cells. The discovery, from Cancer Research UK's London Research Institute (LRI; now part of the Francis Crick Institute), may aid in research into new ways to target leukaemia.
"The blood system is responsible for many different functions, including the distribution of oxygen throughout the body and the maintenance of an effective immune system," explained Dominque Bonnet of LRI. "Much of the regulation of the system occurs at the molecular level in the haematopoetic stem cells, which are found in the bone marrow."
Hematopoietic stem cells are exposed to low levels of oxygen in the bone marrow, and proteins known as hypoxia-inducible factors (HIFs) are the main regulators of cells' responses to this oxygen variation.
It was already known that HIF-1 plays a major role in maintaining stem cell populations in mice, but the role of HIF-2alpha was unclear.
To investigate, Dr Bonnet and her team at LRI worked with colleagues from INSERM and Bordeaux Segalen University in Bordeaux, France, and Barts Cancer Institute at the Queen Mary University of London. They took haematopoetic stem cells from umbilical cord blood samples and blocked the production of HIF-2alpha in these, before transplanting the cells into mice.
This revealed that HIF2-alpha was essential to the survival of the stem cells.
Further experiments in normal haematopoetic stem cells and in leukemic cells showed that HIF-2alpha protected both cell types from death when they were exposed to stress.
Dr Bonnet said: "This work enabled us to further understand the pathway through which HIF-2alpha acts. This has given us a better understanding of the regulation of the blood system, including how this might be used to target leukaemia cells."
The paper, HIF-2a Protects Human Hematopoietic Stem/Progenitors and Acute Myeloid Leukemic Cells from Apoptosis Induced by Endoplasmic Reticulum Stress, is published in Cell Stem Cell.
