RXR: A key protein in the balanced production of different blood cells

In the regulation of hematopoietic stem cells—which are the immature stem cells that produce all the blood cell lineages—the cell protein retinoid X receptor (RXR) is an important element. RXR makes sure that these cells stay fit and young, eventually decreasing the threat of developing myeloproliferative syndromes with aging.

The research was performed by a team at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) working in collaboration with scientists at Cincinnati Children’s Hospital. The research findings show that the supervisory action of RXR on hematopoietic stem cells is needed for the regulation of a balanced generation of the spectrum of blood cell types all through the lifetime.

The research results were published in the journal Blood and could have therapeutic inferences for disorders that have an extreme proliferation of myeloid blood cells, such as in the case of some blood and cardiovascular system diseases.

RXR serves as a nutritional sensor of lipids and vitamin A derivatives, modifying the expression of the gene and influencing key biological functions such as metabolism, immunity, and cell differentiation. Modifying the activation or expression of RXR is associated with the development of inflammatory and metabolic diseases that affect many physical functions, along with the cardiovascular system.

Blood cells come with a short lifetime, and for the same reason, “they must be continuously replenished from a small reservoir of hematopoietic stem cells located in the bone marrow,” detailed Dr Mercedes Ricote, who heads the Nuclear Receptor Signaling group at the CNIC. Nevertheless, the hematopoietic stem cells’ replicative capacity is limited; hence, they should be upheld in an inactive state and divide in a highly regulated way to guarantee that they do not get exhausted too early.

In the study reported in Blood, Dr Ricote’s group and the team headed by Dr Jose Cancelas at Cincinnati Children's Hospital show that the RXR’s elimination from hematopoietic stem cells in mice activates chronic expansion of a subgroup of cells skewed towards the myeloid lineage and megakaryocytes—which are the progenitors of blood platelets. This led to a shortfall of the lymphoid lineage and the progress of myeloproliferative syndrome with the aging of these mice.

The study, whose first authors are Dr Mª Piedad Menéndez-Gutiérrez and Jesús Porcuna (CNIC), demonstrates that the surplus generation of inflammatory myeloid cells in the RXR-deficient mice leads to the invasion by the cells of numerous tissues, specifically the lung, where they cause extreme damage, resulting in the premature death of these mice.

Association with Dr Sánchez-Cabo of the CNIC Bioinformatics Unit and Dr Salomonis (Cincinnati Children’s Hospital) permitted the use of the recent generation massive sequencing techniques and exhaustive analysis of gene expression and DNA structure in hematopoietic stem cells.

Thanks to this analysis, we were able to demonstrate that deletion of RXR in young mice causes the DNA in their hematopoietic stem cells to adopt an open and active conformation, resulting in the expression of genes typical of old cells and the activation of genes regulated by the oncogene MYC, an important protein in the control of hematopoietic stem cell division.”

Dr Mª Piedad Menéndez-Gutiérrez, Study First Author, Spanish National Centre for Cardiovascular Research

“We also generated mice deficient for both MYC and RXR, allowing us to conclude that the activation of MYC is the direct cause of the hyperproliferation of hematopoietic stem cells lacking RXR,” she added.

The scientist underline the likelihood of modulating RXR activity in hematopoietic stem cells via the drug usage; some of the drugs are already employed to cure cutaneous lymphomas. “Our study could have therapeutic implications for conditions characterized by excessive proliferation of myeloid cells, such as some diseases of the blood and cardiovascular systems. Moreover, our findings suggest that the modulation of RXR could be exploited to expand hematopoietic stem cells for therapeutic or regenerative purposes,” concluded Jesús Porcuna.