Figure 2. MPN-associated mutant kinases block normal induction of apoptosis after DNA damage.

In a healthy cell (depicted on the left), the presence of DSBs induces increased NHE-1 expression, by a mechanism that remains to be elucidated. The resulting ion flux via this antiport protein increases the intracellular pH, leading to the deamidation of Bcl-x_L and programmed cell death. In contrast, BCR/ABL or JAK2V617F expression in a mutated cell (depicted on the right) results in nuclear translocation of activated JAK2, phosphorylation of histone H3 on tyrosine-41, and the displacement of HP1α from heterochromatin. This, combined with the generation of reactive oxygen species (ROS) by activated JAK2, is likely to result in an increase in number of DSBs, and inhibition of apoptosis by the prevention of NHE-1 up-regulation, noted in vitro and in vivo. As a consequence of these two alterations, MPN cells would accumulate more mutations, some of which may provide an in vivo proliferative advantage.