A JAK-in-the-cell cycle

In this issue of Blood, Gautier and colleagues describe a novel signaling pathway in which deregulated JAK2 activity augments expression of a key regulator of the cell cycle, the CDC25A phosphatase, via a translational mechanism.¹ 

Six years ago, the identification of an activating point mutation in the JAK2 kinase, JAK2^V617F, in a large majority of patients with myeloproliferative neoplasms (MPNs) provided a significant advance in our understanding of the molecular pathogenesis of these disorders. As is often the case, however, this seminal discovery led to more questions, many of which remain unanswered. One key controversy is whether, and if so, how, the JAK2^V617F allele provides a proliferative advantage to the cell that incurs the mutation. While it was reported earlier that the JAK2^V617F mutation does not provide a proliferative advantage during in vitro expansion,²  a recent study demonstrates a proliferative advantage at the single cell level, especially for those cells that have undergone conversion to the homozygous mutant state.³  In addition, mature compartments display higher JAK2^V617F allele burdens than CD34-positive stem cells, supporting the hypothesis that the mutant kinase provides a proliferative advantage during maturation.^3-5 

Here, Gautier and colleagues provide a significant contribution to our understanding of altered JAK2^V617F function and its effect on the cell cycle in MPN cells. They report that the CDC25A phosphatase, whose activity stimulates completion of the G1 phase and activation of DNA synthesis, is overexpressed in MPN patients' cells and that this increase in CDC25A levels is dependent on augmented JAK2 signaling. Interestingly, it is not the “classic” JAK2 signaling via activation of STAT transcription factors and increased transcription of target genes that raises CDC25A levels in MPN cells. Rather, the authors show that JAK2^V617F increases CDC25A translation. This is effected by a novel signaling pathway in which JAK2^V617F decreases phosphorylation of elongation factor eIF2α, thereby retaining or prolonging its activity, resulting in increased CDC25A translation. Importantly, pharmacologic inhibition of JAK2^V617F-mediated eIF2α dephosphorylation decreased proliferation of primary MPN cells. Furthermore, growth of EPO-independent erythroid colonies (so-called endogenous erythroid colonies [EECs]), a pathognomonic hallmark of polycythemia vera,⁶  was selectively and significantly inhibited by addition of a pan-CDC25 inhibitor. EPO-dependent growth of JAK2 wt and healthy control cells was not affected, although these data await verification on a larger number of samples. These data demonstrate that mutant JAK2^V617F actively influences cell-cycle regulation, thereby promoting cell proliferation. Notably, the study establishes CDC25A as a novel JAK2^V617F target and suggests that its inhibition may impede growth of the MPN clone.

After the initial discovery of the JAK2^V617F mutation, hopes were high that a targeted therapy for MPN patients, similar in efficacy to the tyrosine kinase inhibitors that have changed the paradigm of CML treatment, was within reach. Six years later, the first JAK2 inhibitor, Ruxolitinib, has gained FDA approval but, while very effective at ameliorating disease symptoms, it does not appear to alter the natural history of these diseases. In particular, its effect on JAK2^V617F allele burden, widely assumed to reflect the size of the neoplastic clone, is limited.⁷  Therefore, novel strategies, most likely involving novel targets, are required to foster the development of innovative therapies for MPN patients. Because, as demonstrated by the use of a pan-CDC25 inhibitor in this study, the phosphatase CDC25A is amenable to pharmacologic inhibition, and healthy hematopoiesis appears largely unaffected by this intervention, the paper by Gautier et al provides a promising lead toward the exploration of alternative targets for rational drug design in MPN treatment.