JAK2 V617F Mutation in Non-CML Myeloproliferative Neoplasms
The JAK2 V617F mutation is the gene mutation most commonly used for diagnosis of non-CML myeloproliferative neoplasms (MPNs). 1
Prevalence of JAK2 V617F in Non-CML MPNs
JAK2 V617F is found with varying frequency across different non-CML MPNs:
- Polycythemia vera (PV): Present in >90-95% of cases 1, 2
- Essential thrombocythemia (ET): Present in ~60% of cases 1, 2
- Primary myelofibrosis (PMF): Present in ~60% of cases 1, 2
Diagnostic Significance
The JAK2 V617F mutation serves as a major diagnostic criterion in the WHO classification for non-CML MPNs:
- For PV: JAK2 V617F or functionally similar mutations (like JAK2 exon 12) are included as a major criterion 1
- For ET: Demonstration of JAK2 V617F or other clonal markers is one of the four required diagnostic criteria 1
- For PMF: JAK2 V617F detection helps establish clonality 1
Other Relevant Mutations in Non-CML MPNs
While JAK2 V617F is the most common mutation, other mutations can be found in JAK2-negative cases:
- MPL mutations (W515L, K, or A): Found in 3-5% of ET and 5-8% of PMF patients 1, 2
- CALR mutations: Present in 60-80% of JAK2 and MPL unmutated ET and PMF patients 1
- About 10-15% of ET and PMF patients remain "triple negative" (no JAK2, MPL, or CALR mutations) 2
Clinical Implications
The presence of JAK2 V617F has important clinical implications:
- Excludes reactive forms of erythrocytosis, thrombocytosis, and myelofibrosis 2
- Provides definitive evidence of clonality, eliminating consideration of reactive processes 1
- May correlate with disease phenotype and clinical features 3
- Patients with JAK2 V617F mutation may require cytoreductive therapy more often 4
Detection Methods
JAK2 V617F can be detected through various methods:
- Qualitative methods: ARMS-PCR (Amplification Refractory Mutation System-PCR) 3
- Quantitative methods: Real-time quantitative PCR 3
- Direct sequencing 5
- Immunohistochemistry for phospho-STAT5 expression (downstream effect of JAK2 activation) 4
Differential Diagnosis
The presence of specific genetic markers helps differentiate between various myeloid neoplasms:
- BCR-ABL1 fusion gene (Philadelphia chromosome): Diagnostic of CML 1
- JAK2 V617F: Diagnostic of non-CML MPNs 1
- ADAMTS13 deficiency: Associated with thrombotic thrombocytopenic purpura, not MPNs
In summary, JAK2 V617F mutation testing has revolutionized the diagnosis of non-CML MPNs, providing an objective molecular marker that helps distinguish these neoplasms from reactive conditions and other myeloid disorders.