Myelodysplastic syndromes: scientists close to find a solution

Myelodysplastic syndromes are linked to a dysfunction of a gene involved in the metabolism and oxygenation of blood cells. This makes the HIF1A gene a potential therapeutic target.

A team of scientists from Cincinnati Children's Hospital Center may be solving the mystery surrounding the origins of a group of complex, heterogeneous, currently incurable blood diseases that can lead to leukemia. Myelodysplastic syndromes are associated with a number of genetic mutations and are considered to be one of the most complex blood diseases. It is also a pre-cancerous situation.

Myelodysplastic syndromes affect hematopoietic stem cells in the bone marrow. According to Gang Huang, principal investigator of this new study, a new gene has been identified in these cells that would be able to trigger the different biological processes at the origin of different types of myelodysplastic syndromes observed in patients.

The mechanism involved would be that of a paradoxical activation in the bone marrow of the HIF1A gene, a gene involved in the metabolism and oxygenation of precursor cells of blood cells. The results are published in the journal Cancer Discovery.

Myelodysplastic syndromes choke the bone marrow

Known as myelodysplastic syndromes (MDS), these syndromes are responsible for the appearance of immature cells in the bone marrow, which marrow becomes dysfunctional with insufficient production of healthy mature cells.

Immature blood cells, called blasts, do not work properly. They accumulate in the bone marrow and in the blood where there are therefore fewer red blood cells (anemia), white blood cells (leucopenia) and platelets (thrombocytopenia) healthy. The main risk is that of a progression to leukemia.

No cure for most patients

The only current treatments are aimed essentially at offsetting the deleterious effects of insufficient production of healthy blood cells. Some molecules directed against abnormalities observed during myelodysplastic syndromes are in the test phase. But the only real cure today is bone marrow transplantation.

Unfortunately, the frequency of myelodysplastic syndromes increases with aging and the median age of patients is about 70 years. Thus, bone marrow transplantation is only possible in a very limited number of cases, not least because the older people with this disease are not healthy enough to tolerate hematopoietic stem cell transplantation.

A gene regulating metabolism and oxygen

"We know that the genomes of patients with myelodysplastic syndromes have recurrent mutations in different transcriptional, epigenetic and metabolic regulators, but the incidence of these mutations is not directly correlated with the disease when it appears." "Our study shows that dysfunctions of HIF1A gene activation could cause the various medical problems that doctors observe in patients with myelodysplastic syndromes."
The HIF1A gene (hypoxia inducible factor 1) is a transcription factor, a regulatory gene that tells other genes what to do. HIF1A therefore plays a vital role in the cells' response to metabolic and oxygen rate changes. As a result, it affects the functioning of more than a thousand genes. This includes a vital role in regulating the biological functions of hematopoietic stem cells that produce blood cells in the bone marrow.

The central role of the regulator gene HIF1A

Huang and his colleagues first have the constant involvement of HIF1A gene dysfunction by studying cells from patients with myelodysplastic syndrome through in-depth analysis.
They then demonstrated on different animal models that dysregulation of the HIF1A gene played a central role in the appearance of different types of myelodysplastic syndromes, their complications and their symptoms.

Finally, by experimentally eliminating HIF1A signaling in a mouse model of myelodysplastic syndrome, researchers have shown that inhibition of the HIF1A gene removes many of the symptoms usually observed.

Possible therapeutic target

Although the researchers insist that further research is needed before knowing whether their results will be clinically useful, their study indicates that the HIF1A gene is a potential therapeutic target for a disease where the treatments are essentially palliative.

The main problem is that most currently available HIF1A inhibitors are also targeting a second related molecule, called HIF2A. This is what prevents the use of these inhibitors in patients with myelodysplastic syndrome.

Video: What is MDS? (December 2019).