What is a JAK2 (Janus kinase 2) positive myeloproliferative neoplasm?

From the Guidelines

JAK2 positive myeloproliferative neoplasm (MPN) is a group of blood cancers characterized by the overproduction of blood cells in the bone marrow due to a mutation in the Janus kinase 2 (JAK2) gene, and the most recent and highest quality study recommends that treatment depends on the specific type of MPN and may include phlebotomy, low-dose aspirin, hydroxyurea, or JAK inhibitors like ruxolitinib 1.

Key Characteristics of JAK2 Positive MPNs

• The JAK2 V617F mutation is the most common mutation, causing the JAK2 protein to remain constantly active, leading to uncontrolled blood cell production.
• JAK2 positive MPNs include polycythemia vera (excess red blood cells), essential thrombocythemia (excess platelets), and primary myelofibrosis (bone marrow scarring).
• These conditions increase the risk of blood clots, bleeding, and can potentially transform into acute leukemia.

Diagnosis and Treatment

• The JAK2 mutation testing is crucial for diagnosis, with approximately 95% of polycythemia vera cases and 50-60% of essential thrombocythemia and primary myelofibrosis cases testing positive for this mutation 1.
• Treatment recommendations include:

• Phlebotomy (blood removal) for polycythemia vera
• Low-dose aspirin for vascular symptoms or observation
• Hydroxyurea to reduce cell counts
• JAK inhibitors like ruxolitinib for severe cases or as second-line therapy
• Allogeneic stem cell transplantation for transplant-eligible patients with high or intermediate-2 risk score, or those with intermediate-1 risk score who present with refractory, transfusion-dependent anemia, blasts in peripheral blood > 2%, adverse cytogenetics, or high-risk mutations 1.

Management and Monitoring

• Patients require regular monitoring of blood counts and symptoms, as these are chronic conditions that typically progress slowly but require lifelong management.
• The European LeukemiaNet (ELN) consortium recommends revised management recommendations, including lower threshold values for hemoglobin and hematocrit and bone marrow examination for diagnosis of polycythemia vera, and the search for complementary clonal markers for the diagnosis of myelofibrosis 1.

From the Research

Definition of JAK2 Positive Myeloproliferative Neoplasm

• JAK2 positive myeloproliferative neoplasm refers to a group of disorders characterized by the overproduction of cells from one or more myeloid lineages, associated with a unique somatic 1849G>T JAK2 mutation (encoding V617F) 2.
• This mutation is believed to be a critical driver of excess proliferation and is found in more than 95% of cases of polycythemia vera, and roughly half of essential thrombocythemia and primary myelofibrosis 2.

Characteristics of JAK2 Positive Myeloproliferative Neoplasm

• JAK2 positive myeloproliferative neoplasms include essential thrombocythemia, polycythemia vera, and primary myelofibrosis, which can be divided into distinct subtypes based on the presence of the JAK2V617F mutation 3.
• The JAK2V617F mutation leads to a JAK2 constitutive activation, which is a driver of myeloproliferation 4.
• The presence of the JAK2 V617F mutation is considered the most important criterion in the diagnosis of breakpoint cluster region-Abelson fusion oncogene-negative neoplasms and is thus used as a clonal marker 5.

Significance of JAK2 Mutation Positivity

• JAK2 mutation positivity is significant in the diagnosis, prognosis, and therapy of myeloproliferative neoplasms 3.
• The JAK2 signaling pathway is a central target for therapy in myeloproliferative neoplasms, and targeting JAK2 and its signaling may be a promising approach for treatment 4.
• However, the development of targeted therapy remains a challenge due to the necessary physiological role of JAK2 and the involvement of multiple mutations 6.