What is the purpose of JAK2 (Janus Kinase 2), MPL (Myeloproliferative Leukemia Virus), and CALR (Calreticulin) gene monitoring?

JAK2, MPL, and CALR Monitoring in Myeloproliferative Neoplasms

JAK2, MPL, and CALR gene mutation testing is essential for the diagnosis of myeloproliferative neoplasms (MPNs) and has significant prognostic value for determining disease course, risk of complications, and guiding treatment decisions. 1

Diagnostic Role

Primary Diagnostic Markers

• JAK2 V617F mutation: Present in >90-95% of polycythemia vera (PV), ~60% of essential thrombocythemia (ET), and ~60% of primary myelofibrosis (PMF) cases 1
• JAK2 exon 12 mutations: Found exclusively in 2-4% of PV patients who are negative for JAK2 V617F 1
• CALR mutations: Present in 60-80% of JAK2 and MPL unmutated ET and PMF patients 1
• MPL mutations (W515L, K, or A): Found in 3-5% of ET and 5-8% of PMF patients 1

Diagnostic Algorithm

1. Test for JAK2 V617F mutation first
2. If negative and suspecting PV, test for JAK2 exon 12 mutations
3. If negative and suspecting ET or PMF, test for CALR and MPL mutations
4. Approximately 10-15% of ET and PMF patients remain "triple negative" (no JAK2, MPL, or CALR mutations) 1

Prognostic Significance

The mutation status has important prognostic implications:

• JAK2 V617F: Associated with intermediate prognosis and higher risk of thrombosis compared to patients with CALR mutations 2
• MPL W515L/K: Similar to JAK2, associated with intermediate prognosis and higher thrombotic risk 2
• CALR: Associated with improved survival compared to JAK2 mutation and "triple-negative" PMF, and lower risk of thrombosis compared to JAK2 mutation 2
• CALR Type 1/Type 1-like: Better overall survival compared to CALR type 2/type 2-like and JAK2 V617F mutation 2
• "Triple Negative": Associated with inferior leukemia-free survival compared to patients with JAK2 and/or CALR mutations, and inferior overall survival compared to patients with CALR mutations 2

Monitoring Value

Monitoring JAK2, MPL, and CALR mutations serves several purposes:

1. Disease progression assessment: Changes in mutant allele burden may indicate disease progression 2
2. Treatment response: Particularly useful in the setting of allogeneic stem cell transplantation (alloSCT) where monitoring JAK2V617F allele burden helps predict relapse 2
3. Transformation risk: Monitoring can help identify patients at risk for leukemic transformation 2
4. Therapeutic decisions: Mutation status may influence treatment choices, particularly for targeted therapies 1

Clinical Applications

• Risk stratification: Mutation status is incorporated into prognostic scoring systems to guide treatment decisions 2, 1
• Treatment selection: Certain mutations may predict response to specific therapies, such as JAK inhibitors 1
• Monitoring disease evolution: Sequential testing can detect clonal evolution or emergence of additional mutations 3
• Post-transplant monitoring: JAK2V617F allele burden monitoring is valuable for predicting relapse after alloSCT 2

Important Considerations

• Low JAK2 V617F allele burden (<1%) may coexist with additional CALR or MPL mutations, suggesting the presence of different malignant clones 3
• In cases with low JAK2 V617F allele burden, additional testing for CALR and MPL mutations is advisable 3
• Combined mutations (though rare) may have different prognostic implications and should be monitored separately 3
• Regular monitoring should include assessment of spleen size, blood counts, constitutional symptoms, and bone marrow morphology alongside molecular testing 2

By incorporating JAK2, MPL, and CALR mutation testing into clinical practice, physicians can better diagnose, risk-stratify, and manage patients with MPNs, ultimately improving outcomes related to morbidity, mortality, and quality of life.