Heterodimeric JAK-STAT Activation as a Mechanism of Persistence to JAK2 Inhibitor Therapy

The identification of somatic activating mutations in JAK21–4 and in the thrombopoietin receptor (MPL)5 in the majority of myeloproliferative neoplasm (MPN) patients led to the clinical development of JAK2 kinase inhibitors6,7. JAK2 inhibitor therapy improves MPN-associated splenomegaly and systemic symptoms, but does not significantly reduce or eliminate the MPN clone in most MPN patients. We therefore sought to characterize mechanisms by which MPN cells persist despite chronic JAK2 inhibition. Here we show that JAK2 inhibitor persistence is associated with reactivation of JAK-STAT signaling and with heterodimerization between activated JAK2 and JAK1/TYK2, consistent with activation of JAK2 in trans by other JAK kinases. Further, this phenomenon is reversible, such that JAK2 inhibitor withdrawal is associated with resensitization to JAK2 kinase inhibitors and with reversible changes in JAK2 expression. We saw increased JAK2 heterodimerization and sustained JAK2 activation in cell lines, murine models, and patients treated with JAK2 inhibitors. RNA interference and pharmacologic studies demonstrate that JAK2 inhibitor persistent cells remain dependent on JAK2 protein expression. Consequently, therapies that result in JAK2 degradation retain efficacy in persistent cells and may provide additional benefit to patients with JAK2-dependent malignancies treated with JAK2 inhibitors

Heterodimeric JAK-STAT Activation as a Mechanism of Persistence to JAK2 Inhibitor Therapy

The identification of somatic activating mutations in JAK21–4 and in the thrombopoietin receptor (MPL)5 in the majority of myeloproliferative neoplasm (MPN) patients led to the clinical development of JAK2 kinase inhibitors6,7. JAK2 inhibitor therapy improves MPN-associated splenomegaly and systemic symptoms, but does not significantly reduce or eliminate the MPN clone in most MPN patients. We therefore sought to characterize mechanisms by which MPN cells persist despite chronic JAK2 inhibition. Here we show that JAK2 inhibitor persistence is associated with reactivation of JAK-STAT signaling and with heterodimerization between activated JAK2 and JAK1/TYK2, consistent with activation of JAK2 in trans by other JAK kinases. Further, this phenomenon is reversible, such that JAK2 inhibitor withdrawal is associated with resensitization to JAK2 kinase inhibitors and with reversible changes in JAK2 expression. We saw increased JAK2 heterodimerization and sustained JAK2 activation in cell lines, murine models, and patients treated with JAK2 inhibitors. RNA interference and pharmacologic studies demonstrate that JAK2 inhibitor persistent cells remain dependent on JAK2 protein expression. Consequently, therapies that result in JAK2 degradation retain efficacy in persistent cells and may provide additional benefit to patients with JAK2-dependent malignancies treated with JAK2 inhibitors

The Relationship between the Ability to Cope with Unexpected Perturbations and Mechanical and Functional Ankle Instability

We aimed to examine the associations between ankle instability, identified by mechanical and functional assessments, and an individual’s ability to cope unexpected perturbations. Sixty students were assessed for five different mechanical/functional ankle instability assessments: the Cumberland Ankle Instability Tool (CAIT), history of previous ankle sprains, the Ankle Instability Instrument (AII) questionnaires, proprioception ability, and mechanical instability. The point where participants lost postural balance due to an unexpected perturbation was recorded when participants were standing on BalanceTutor-Treadmill® with eyes open-SO, eyes closed-SC, tandem-dominant-leg forward-TD, tandem non-dominant-leg forward-TND, single-leg same side-SLSS, single-leg opposite side-SLOS and walking. Significant correlations were found between: CAIT and perturbation in the TND-position; AII scores and perturbations in TD and TND positions; ankle sprains and perturbations in SC, ND, and NTD positions; and proprioception ability and perturbations in SO, SC, TD, TND, and walking (p p < 0.05). Functional ankle instability and proprioception ability were associated with the ability to cope with unexpected perturbations when starting from different standing/walking positions. Individuals with ‘stable’ ankles in most mechanical/functional assessments had better ability to cope perturbations than those with ‘unstable’ ankles