(CORDIS) — Researchers from Finland and the United States have shed light on the mechanisms at play in certain devastating haematological disorders, paving the way for the development of new disease-specific treatments.
The team, who present their findings in the journal Nature Structural & Molecular Biology, uncovered mutations in a protein structure in enzymes that convert the cell-signalling molecules that regulate blood cell formation.
These small cell-signalling protein molecules are called cytokines and they regulate blood cell formation and activity via a signal pathway mediated by Janus kinases (JAKs), a family of enzymes.
Previous studies have shown that mutations in JAKs can lead to the onset of severe haematological disorders as well as immunological diseases. These mutations are concentrated in the pseudokinase domain, a dual-specificity protein kinase that negatively regulates cytokine signalling.
Scientists in the field have long tried to get to the bottom of the mysterious structural nature of the pseudokinase domain of JAKs, as knowing more about how it is formed can help us understand more about the haematological disorder-causing pathogenic mutations that occur there.
Now, in this new study, led by Professor Olli Silvennoinen from the University of Tampere in Finland, the team has successfully determined the three-dimensional atomic-level structure of both the normal and the pathogenic pseudokinase domain. The team, which includes researchers from New York University School of Medicine, Columbia University and research laboratory D.E. Shaw Research, describe the structure of the pseudokinase domain of JAKs in detail.
They are the first group to successfully reveal the pseudokinase domain’s enzymatic mechanisms at the atomic level.
Professor Silvennoinen has many years of experience investigating JAKS: in the early 1990s he successfully cloned the JAK2 gene and demonstrated its activity in the signalling pathways of erythropoietin and interferon. Since then determining and characterising the regulatory function of the pseudokinase domain has been the central focus of his work.
The team also managed to determine the structural change, caused by mutation in JAK2, which gives rise to common myeloproliferative diseases, such as polycythemia vera, essential thrombocythemia and myelofibrosis.
Broadly speaking, myeloproliferative diseases are a group of diseases of the bone marrow in which excess cells are produced.
Polycythemia vera and essential thrombocythemia are blood disorders characterised by an overproduction of red blood cells or platelets, whereas myelofibrosis is a disorder that causes scar tissue to accumulate in the bone marrow.
Symptoms of myelofibrosis include: unexpected weight loss; abdominal pain due to an enlarged liver or spleen; unusual bruising or bleeding; tiredness caused by anaemia (a lack of red blood cells); and frequent and persistent infections caused by a lack of white blood cells that normally fight infection.
The team hope that their findings can go some way to developing new, targeted treatments for some of these disorders.