JAK2negative

JAK2negative refers to the absence of a JAK2 gene mutation, most commonly the JAK2 V617F activating mutation, in individuals evaluated for myeloproliferative neoplasms (MPNs) or related disorders. The JAK2 V617F mutation stimulates the JAK-STAT signaling pathway and is a key molecular feature used to support a diagnosis of certain MPNs.

Testing and variants are central to defining JAK2negative status. JAK2 V617F is detected by allele-specific PCR and similar methods, while some patients with polycythemia vera (PV) may harbor JAK2 exon 12 mutations instead of V617F. In essential thrombocythemia (ET) and primary myelofibrosis (PMF), roughly half of patients carry JAK2 V617F, with other cases having CALR or MPL mutations or being JAK2-negative. The term JAK2negative may therefore reflect true absence of JAK2 mutations or the presence of other activating mutations driving the disease.

JAK2negative disease can occur in a spectrum that includes PV, ET, PMF, and other MPNs. In many patients, testing for CALR and MPL mutations is also performed, because a substantial subset of JAK2-negative cases harbor CALR or MPL mutations. A subset of MPNs remains triple-negative, lacking JAK2, CALR, and MPL mutations, which can present distinct diagnostic and prognostic considerations.

Impact on management and prognosis is variable. JAK2 status alone does not determine treatment; risk stratification, clinical features, and other mutations guide decisions. JAK inhibitors such as ruxolitinib are used for certain advanced or symptomatic MPNs regardless of JAK2 status, reflecting pathway activity beyond a single mutation.