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Editorials
JAK2V617F have an increased propensity to neutrophil extra- References
cellular trap formation and thrombosis. Inhibition of JAK- STAT signaling by ruxolitinib abrogated neutrophil extra- cellular trap formation and reduced thrombosis in this murine model.
The current report of Guy et al. as well as the other reports referred to in this Commentary each delineate the increasingly plausible role of various cell adhesion mole- cules (selectins and integrins) in MPN-associated thrombo- sis and in some cases evolution to MF. The question remains, how relevant are these observations in disease models to the pathophysiology of MPN in patients? This is especially relevant to the work dealing with JAK2V617F+ EC. Sozer et al.16,17 previously documented that angiogenic monocytes as well as true EC were JAK2V617F+ in PV patients with splanchnic vein thromboses. Using laser capture microdissection they demonstrated that the EC within the hepatic veins of some PV patients with hepatic vein throm- bosis were JAK2V617F+. Furthermore, Rosti et al.18 reported that splenic vein EC were JAK2V617F+ in 67% of patients with MF. To better understand the significance of these intriguing experimental findings, the frequency of JAK2V617F+ MPN patients with mutated EC, the extent of the distribution of these JAK2V617F+ EC within the vasculature of various tissues, and the relationship of these findings to the incidence of thrombosis in MPN require evaluation in larger numbers of patients. It will also be interesting to determine whether other driver mutations in MPN, such as calreticulin, share the same properties which might explain, in part, the differ- ent propensity to develop thrombosis relative to that in JAK2V617F-mutated patients. The increased propensity to develop thrombosis in MPN patients is likely multifactorial in origin. An elevated hematocrit and a pro-inflammatory state, as well as a series of cellular interactions mediated by cell adhesion molecules that are expressed by red cells, platelets, leukocytes, monocytes and EC, may all play a role (Figure 1), and combinations of these events at any one time may further increase the risk of developing a thrombotic event. Most importantly, this recent round of studies pro- vides a rationale for the evaluation of blocking antibodies to P-selectin, VLA-4 and LFA-1, which in part are already in clinical use for other conditions,19-21 to further reduce the incidence of not only thrombotic events but also disease progression beyond that achieved with the presently avail- able therapeutic options. The outcomes of such proposed clinical trials, which are at best presently in the planning stages, will be closely watched. Such studies will allow us to assess the importance of each of these membrane pro- teins in the development of life-threatening clinical events in MPN patients and are likely to increase the therapeutic options for such patients.
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haematologica | 2019; 104(1)