How does the JAK2 V617F mutant induce EPO hypersensitivity?
At present, it is unknown whether the mutant JAK2 requires a cytokine receptor to scaffold and signal or whether it signals independently of receptor association. In JAK2-deficient cells, the mutant JAK2 could initiate a signal alone but it also transduces a signal from the EpoR upon Epo addition,26 demonstrating that the mutant JAK2 binds to the EpoR cytoplasmic domain and transduces a ligand-dependent signal. Since both the mutant JAK2 and EpoR are expressed normally at low levels, it is likely that the mutant JAK2 uses and amplifies the signal normally triggered by EpoR. In the same cells or in retrovirally transduced Ba/F3 cells, the mutant JAK2 was able to promote trafficking of the EpoR to the cell-surface, albeit at a lower efficiency than a wild-type JAK2. Further experiments are still required to establish whether the mutant JAK2 also promotes down-regulation of activated EpoRs and whether the lower enhancement of trafficking is not due to this effect. Our model would predict
