MAPK flagging: Pathway | Leukemia

By deactivating a part of the MAPK signaling pathway, specialists were able to reduce the number of leukemia cells in blood and bone marrow. According to a study published in Leukemia, combining Janus kinase 2 (JAK2) inhibitors with a targeted blockade of the extracellular signal-regulated kinase (ERK) 1/2 pathway improved therapeutic outcomes.

In myeloproliferative neoplasms, a type of chronic leukemia, the body produces an excess of blood cells, including erythrocytes, platelets, and granulocytes. This condition can lead to symptoms like thrombosis, an enlarged spleen, weight loss, bone pain, and fatigue. The condition is triggered by mutations that keep the JAK2 tyrosine kinase constantly active, signaling the bone marrow to produce blood cells continuously.

JAK2 inhibitors have been in use for nearly a decade, but according to Dr. Sara Christina Meyer, MD, PhD, attending physician in Hematology at the University Hospital of Basel, the treatment has not fully met expectations. "We are addressing the question of why this targeted therapy is not more effective," said Meyer in a press release.

The MAPK signaling pathway, which is involved in the development of various cancers, is regulated by JAK2 in myeloproliferative neoplasms. Researchers used three experimental models to determine whether deactivating both ERK1/2 and JAK2 would be more effective than targeting JAK2 alone. These models included leukemia cell cultures, mouse models for myeloid leukemia, and blood and bone marrow samples from patients.

According to the researchers, JAK2 inhibitor treatment was enhanced when ERK1/2 was also targeted. The treatment resulted in a reduction in spleen size in mouse models and decreased blood cell production across all three models. Additionally, the number of leukemia cells in blood and bone marrow was reduced, which could potentially alter the long-term course of the disease, an outcome rarely achieved by JAK2 inhibitors alone.

Due to the promising efficacy of this combination in early testing, the treatment is now being tested in a global phase 1/2 clinical trial. This combination therapy is currently being used in a small number of patients, and researchers hope to obtain results in the coming months. "As a clinician and researcher, my focus is on improving treatments. My main motivation is to find something that works in the lab and can truly help people with leukemias like myeloproliferative neoplasms," Meyer added.