Myeloproliferative neoplasms (MPNs) are a group of rare but malignant diseases affecting the bone marrow that result in increased production of red blood cells, white blood cells, and platelets. MPNs are caused by mutations (genetic changes) in the hematopoietic cells in the bone marrow, occur either due to genetic predisposition or environmental factors. In the recent research, scientists have identified a protein that influences the mutation process that leads to MPN.
MPNs are chronic diseases with only 1 to 2 new cases diagnosed per 100,000 people every year. MPNs can affect people at any age, but they are most common among adults around 60 years old. Men have a slightly higher risk to develop the disease compared to women. Over 80% of patients with MPNs exhibit an acquired point mutation in the gene JAK2. This so-called JAK2V617F mutation causes JAK2, a regulator of cell proliferation, to be constantly turned on. As a result, the affected cell begins to divide out of control - and the illness takes its course.
‘Spleen gets highly enlarged in MPN diseased patients. The absence of CDK6 proteins alleviated the symptoms associated with MPN with the spleen shrinking back to its standard size and disease progression is delayed.’
MPN patients have so far been treated with ruxolitinib, a JAK2 inhibitor. Ruxolitinib effectively controls the symptoms but does not offer a cure, as the malignant stem cell clone is located in the bone marrow and is generally not attacked. Discontinuing the treatment involves a high risk of relapse or progression to AML, a form of leukemia. Therefore, it is of importance to discover new therapeutic approaches.
Significant factor influencing the disease: the protein CDK6
A research team led by Veronika Sexl from Vetmeduni Vienna and Robert Kralovics from CeMM/Medical University of Vienna succeeded in doing just that. Using a mouse model, they identified the protein CDK6 as an important factor influencing the development of JAK2V617F-initiated MPN. "We were able to show that in the absence of CDK6, the proliferation of affected stem cells was reduced and cell death was increased. As a consequence, the absence of CDK6 ameliorated the clinical symptoms and increased life expectancy," says Sexl.
Novel therapeutic approach for MPN patients
The absence of CDK6 clearly attenuates the symptoms in the long term. The spleen, greatly enlarged by the disease, shrinks back to its normal size and the progression of the disease is delayed. Kralovics: "CDK6 is a central signalling node that connects cell cycle control; the activation of the protein NFκB, a master regulator of inflammation; apoptosis, which refers to the programmed cellular death; and malignant stem-cell function. Our work indicates that fine-tuning the level of CDK6 influences this mechanism and could potentially improve the quality of life of MPN patients. This opens up the possibility of a completely novel therapeutic approach."