How a single mutation drives three blood cancers.

JAK2V617F sits in the kinase's pseudokinase domain and disrupts an autoinhibitory loop, leaving JAK2 constitutively active and constitutively phosphorylating STAT5, STAT3, and other downstream effectors. The result is cytokine-independent proliferation of the affected hematopoietic lineages.

The lab's foundational contribution is an inducible JAK2V617F knock-in mouse expressing the mutation from its endogenous promoter. Heterozygous expression alone is sufficient to drive a polycythemia vera-like disease; homozygous expression accelerates progression toward myelofibrosis. The model recapitulates the dose-dependent phenotypic divergence seen in patients and is now a standard tool across the MPN field.

Genetic dissection in this background has identified the critical effectors. STAT5 deletion completely blocks JAK2V617F-induced PV, naming STAT5 as the pivotal downstream node. STAT3, despite being the canonical JAK partner, is dispensable. Tyrosine 201 of JAK2V617F is required for constitutive activation — a structural constraint relevant to inhibitor design.

Cooperating mutations shape disease trajectory. Loss of the polycomb component EZH2 cooperates with JAK2V617F to accelerate myelofibrosis, partly by derepressing HMGA2; HMGA2 in turn drives MF through TGF-β1 and CXCL12 signaling. Loss of the wild-type Jak2 allele in V617F mice worsens disease, mirroring the clinical observation that homozygous patients fare worse.