JAK2 V617F Mutation Detection, Blood
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
The Janus kinase 2 gene (JAK2) codes for a tyrosine kinase (JAK2) that is associated with the cytoplasmic portion of a variety of transmembrane cytokine and growth factor receptors important for signal transduction in hematopoietic cells. Receptor binding by extracellular ligand causes receptor multimerization and brings JAK2 proteins together to allow activation by transphosphorylation. Activated JAK2 then phosphorylates the cytoplasmic portion of the receptor creating a docking site for the latent transcription factor, STAT5, which is also phosphorylated by JAK2. Phosphorylated STAT5 then forms dimers that translocate into the nucleus and initiate transcription of genes ultimately responsible for cell growth and differentiation.
Recently, a point mutation in JAK2 (V617F) was identified in the hematopoietic cells of several chronic myeloproliferative disorders (CMPDs), most frequently polycythemia vera (65%-97%), essential thrombocythemia (25%-55%), and chronic idiopathic myelofibrosis (35%-57%).(1-3) The mutation has been reported at much lower frequency in some other CMPDs, chronic myelomonocytic leukemia and myelodysplastic syndromes.(4) It has not been reported in chronic myelogenous leukemia (CML), normal patients, or reactive cytoses.(1-4) This mutation causes constitutive activation of JAK2 and is thought to play a key role in the neoplastic phenotype. Since it is often difficult to distinguish reactive conditions from the non-CML CMPDs, identification of the JAK2 mutation has diagnostic value. Potential prognostic significance of JAK2 mutation detection in chronic myeloid disorders has yet to be clearly established.
Aiding in the distinction between a reactive cytosis and a chronic myeloproliferative disorder
The results will be reported as 1 of the 3 states:
-Negative for JAK2 V617F mutation
-Below the laboratory cutoff for JAK2 V617F mutation positivity
-Positive for JAK2 V617F mutation
Positive mutation status is highly suggestive of a myeloid neoplasm, but must be correlated with clinical and other laboratory features for definitive diagnosis. Negative mutation status does not exclude the presence of a chronic myeloproliferative disorder or other neoplasm. Results below the laboratory cutoff for positivity are of unclear clinical significance at this time.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
A positive result is not specific for a particular diagnosis and clinicopathologic correlation is necessary in all cases.
A negative result does not exclude the presence of a chronic myeloproliferative disorder or other neoplastic process.
In rare cases, a mutation other than the V617F may be present in an area that interferes with primer or probe binding and cause a false negative result.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
An interpretive report will be provided.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Baxter EJ, Scott LM, Campbell PJ, et al: Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005 March 16;365(9464):1054-1061
2. James C, Ugo V, Le Couedic JP, et al: A unique clonal JAK2 mutation leading to constitutive signaling causes polycythaemia vera. Nature 2005 April 28;434(7037):1144-1148
3. Kralovics R, Passamonti F, Buser AS, et al: A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005;352:1779-1790
4. Steensma DP, Dewald GW, Lasho TL, et al: The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both "atypical" myeloproliferative disorders and the myelodysplastic syndrome. Blood 2005;106:1207-1209