Researchers decode biology of blood and iron disorders mapping out novel future therapies

Two studies led by investigators at Weill Cornell Medical College shed light on the molecular biology of three blood disorders, leading to novel strategies to treat these diseases.
The two new studies propose two new treatments for beta-thalassaemia, a blood disorder which affects thousands of people globally every year. In addition, they suggest a new strategy to treat thousands of Caucasians of Northern European ancestry diagnosed with HFE-related hemochromatosis and a novel approach to the treatment of the rare blood disorder polycythaemia vera.
These research insights were only possible because two teams that included 24 investigators at six American and European institutions decoded the body’s exquisite regulation of iron, as well as its factory-like production of red blood cells.
‘When you tease apart the mechanisms leading to these serious disorders, you find elegant ways to manipulate the system,’ says Dr. Stefano Rivella, associate professor of genetic medicine in pediatrics at Weill Cornell Medical College.
For example, Dr. Rivella says, two different gene mutations lead to different outcomes. In beta-thalassemia, patients suffer from anaemia — the lack of healthy red blood cells — and, as a consequence, iron overload. In HFE-related haemochromatosis, patients suffer of iron overload. However, he adds, one treatment strategy that regulates the body’s use of iron may work for both disorders.
Additionally, investigators found another strategy, based on manipulating red blood cell production, could also potentially treat beta-thalassaemia as well as a very different disorder, polycythaemia vera.
Dr. Rivella and his colleagues tackled erythropoiesis — the process by which red blood cells (erythrocytes) are produced — as a way to decipher and decode the two blood disorders beta-thalassaemia and polycythaemia vera.
Beta-thalassaemia, a group of inherited blood disorders, is caused by a defect in the beta globin gene. This results in production of red blood cells that have too much iron, which can be toxic, resulting in the death of many of the blood cells. What are left are too few blood cells, which leads to anaemia. At the same time, the excess iron from destroyed blood cells builds up in the body, leading to organ damage. In polycythaemia vera, a patient’s bone marrow makes too many red blood cells due to a genetic mutation that doesn’t shut down erythropoiesis — the production of the cells.
The researchers studied both normal erythropoiesis, in which a person makes enough red blood cells to replace those that are old, and a mechanism called stress erythropoiesis, which flips on when a person requires extra blood cells — such as loss of blood from an accident. The hormone erythropoietin (EPO) controls red blood cell production, and can also induce stress erythropoiesis. Iron is also essential, says Dr. Rivella. ‘The two well-known elements needed to switch between normal and stress erythropoiesis are EPO and iron,’ he says.
But Dr. Rivella and his team found that a third player is essential: macrophages, the immune cells that engulf cellular garbage and pathogens. Macrophages had been known to digest the iron left when old blood cells are targeted for destruction, but Dr. Rivella discovered that they also are necessary for stress erythropoiesis. He found macrophages need to physically touch erythroblasts, the factories that make red blood cells, in order for more factories to be created so that they can churn out red blood cells.
‘No one knew macrophages were a part of emergency red blood cell production. We now know they provide fuel to push red blood cell factories to work faster,’ says the study’s lead author Dr. Pedro Ramos, a former postdoctoral researcher at Weill Cornell.
The research team then looked at diseases in which there are too many red blood cell factories. Polycythemia vera was one of the conditions examined. The researchers disabled macrophage functioning in mice with polycythemia vera and found that red blood cell production returned to normal.
In beta-thalassemia, the body increases the number of red blood cell factories to make up for the lack of viable blood cells — a strategy that doesn’t work. As a result, patients develop enlarged spleens and livers due to the overload of erythroblasts in those organs.
The researchers found in mouse models that if they suppress the function of macrophages, the number of blood cell factories revert back to normal levels. However, there was also an additional benefit discovered. One of the functions of macrophages is to put excess recycled iron into erythroblasts. Researchers report if you suppress that function, less iron goes into the red blood cells. ‘So you then make red blood cells that have less iron, and they are now closer in structure to what they should be,’ says Dr. Rivella.
In animal studies, the researchers saw that decoupling macrophages from the erythroblasts not only reduced the number of blood cell factories, but also improved anaemia.
The discovery could be translated into an experimental therapy by finding the molecule that physically binds a macrophage to an erythroblast, and then targeting and inhibiting it. ‘We need macrophages for good health, but it may be possible to decouple the macrophages that contribute to blood disorders,’ Dr. Rivella says. ‘I estimate that up 30 to 40 percent of the beta-thalassaemia population could benefit from this treatment strategy.’
Dr. Rivella also made another connection. He says polycythaemia vera ‘is sort of a tumour of the red cells, because you make too many of them.’ And he notes that previous research on macrophages found that they are very important in cancer metastasis. ‘I see a parallel between the activity of macrophages in supporting the proliferation of cells that are under stress conditions — growing tumors and red blood cells that need to grow,’ he says. ‘It seems to us that macrophages are important in supporting a switch between normal growth and increased growth.’ Weill Cornell Medical College