What is the Origin of JAK2 V617F Mutation?

JAK2 is an acronym for Janus Kinase 2, named after the Roman god Janus for its two-faced, or two-domain, structure. The V617F nomenclature precisely describes the amino acid substitution within the enzyme's sequence. This seminal mutation was discovered in 2005, and its identification fundamentally changed the diagnostic and therapeutic approach to conditions such as polycythemia vera, essential thrombocythemia, and primary myelofibrosis.

What is the Mechanism of JAK2 V617F Mutation?

The mutation's mechanism involves a critical conformational change in the JAK2 protein that prevents the regulatory pseudokinase domain from exerting its normal inhibitory control over the kinase domain. This constant activation results in uncontrolled, cytokine-independent downstream signaling, primarily through the JAK-STAT pathway. The resulting aberrant signal transduction drives the excessive proliferation and prolonged survival of hematopoietic stem cells in the bone marrow, causing the clinical features of MPNs, which are intrinsically linked to systemic hormonal dysregulation of hematopoiesis.

JAK2 V617F Mutation ∞ Area

JAK2 V617F Mutation

Meaning

The JAK2 V617F Mutation is a specific, acquired point mutation in the Janus Kinase 2 gene, which involves the substitution of a valine (V) amino acid with a phenylalanine (F) at position 617 of the protein sequence. This single genetic change results in the constitutive, or persistent, activation of the JAK2 protein, a non-receptor tyrosine kinase. Clinically, this mutation is a crucial diagnostic and prognostic marker for several Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), disorders characterized by the uncontrolled overproduction of blood cells.