New Therapeutic Target for Myeloproliferative Neoplasm

Targeting a specific protein can influence the development of the JAK2 inhibitor, a possible therapeutic target for myeloproliferative neoplasms (MPNs), according to a new report.

MPNs are malignant bone marrow diseases more likely to affect older adults, especially men. Each year, about 1 to 2 new cases are diagnosed per 100,000 people. Genetic mutations in the hematopoietic cells in the bone marrow happen spontaneously because of genetic predispositions or exposure to environmental factors.

Currently, MPN patients are often treated with ruxolitinib, which is a JAK2 inhibitor. Treatment with ruxolitinib controls the symptoms of MPN but is not a cure. Additionally, the study authors said, discontinuing that treatment can lead to a high risk for relapse or progression to forms of leukemia. These risks drove investigators from the University of Veterinary Medicine in Vienna, Austria, to explore new therapeutic approaches.

A majority of MPN patients show an acquired point mutation in the JAK2 gene called JAK2V617F. When this is activated, the JAK2 is constantly flipped “on” and cannot regulate cell proliferation. Affected cells begin to divide out of control and the illness begins, the study authors explained.

In mice models, the investigators learned that the development of JAK2V617F-initiated MPN was influenced by the protein CDK6.

“We were able to show that in the absence of CDK6, the proliferation of affected stem cells was reduced and cell death was increased,” study author Veronika Sexl, MD, Institute of Pharmacology and Toxicology, University of Veterinary Medicine of Vienna, Austria, said in a press release. “As a consequence, the absence of CDK6 ameliorated the clinical symptoms and increased life expectancy.”

Without CDK6, long-term effects of the symptoms of MPN can be reduced. For example, MPN can enlarge the spleen, but after this discovery, the investigators showed that it shrunk to normal size and the MPN disease progression was delayed.

The study authors described CDK6 as a central signaling node that connects cell cycle control, affecting 3 hallmarks of MPN disease. It activates the protein NFkB, which regulates inflammation. It inhibits apoptosis, the programmed cellular death, and it also contributes to 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,” study author Robert Kralovics, PhD, added in the statement. “This opens up the possibility of a completely novel therapeutic approach.”

The study authors added that these findings were not shown in treatment with palbociclib, which they believe indicates that the functions of CDK6 in MPN pathogenesis are largely kinase-independent, they wrote. Because of this, they believe they have found a rationale for targeting CDK6 as a treatment for MPN.

The paper, “Cdk6 coordinates Jak2V617F mutant MPN via NFκB and apoptotic networks,” was published in Blood.