Identification of myeloproliferative neoplasm drug agents via predictive simulation modeling: assessing responsiveness with micro-environment derived cytokines

Previous studies have shown that the bone marrow micro-environment supports the myeloproliferative neoplasms (MPN) phenotype including via the production of cytokines that can induce resistance to frontline MPN therapies. However, the mechanisms by which this occurs are poorly understood. Moreover, the ability to rapidly identify drug agents that can act as adjuvants to existing MPN frontline therapies is virtually non-existent. Here, using a novel predictive simulation approach, we sought to determine the effect of various drug agents on MPN cell lines, both with and without the micro-environment derived inflammatory cytokines. We first created individual simulation models for two representative MPN cell lines; HEL and SET-2, based on their genomic mutation and copy number variation (CNV) data. Running computational simulations on these virtual cell line models, we identified a synergistic effect of two drug agents on cell proliferation and viability; namely, the Jak2 kinase inhibitor, G6, and the Bcl-2 inhibitor, ABT737. IL-6 did not show any impact on the cells due to the predicted lack of IL-6 signaling within these cells. Interestingly, TNFα increased the sensitivity of the single drug agents and their use in combination while IFNγ decreased the sensitivity. In summary, this study predictively identified two drug agents that reduce MPN cell viability via independent mechanisms that was prospectively validated. Moreover, their efficacy is either potentiated or inhibited, by some of the micro-environment derived cytokines. Lastly, this study has validated the use of this simulation based technology to prospectively determine such responses

Jak2 Tyrosine Kinase: A Potential Therapeutic Target for AT1 Receptor Mediated Cardiovascular Disease

Patients with hypertension often manifest a dysregulated renin-angiotensin-aldosterone system (RAAS). Most of the available treatment approaches for hypertension are targeted towards the RAAS including direct renin inhibition, ACE inhibition, angiotensin II type 1 receptor (AT1-R) blockade, and aldosterone receptor antagonism. The Jak2 signaling pathway is intricately coupled to the AT1-R signaling processes involved in hypertension. Here, we review the involvement of Jak2 in the pathogenesis of hypertension, and its potential as a therapeutic target for treatment of AT1-R mediated cardiovascular disease. Jak2 may provide a rational therapeutic approach for patients whose blood pressure is not controlled by standard therapies

Vascular smooth muscle Jak2 deletion prevents angiotensin II-mediated neointima formation following injury in mice

The in vitro treatment of vascular smooth muscle cells (VSMC) with angiotensin II (Ang II) causes Janus kinase 2 (Jak2) to interact with the Ang II type 1 receptor (AT1-R) resulting in enhanced cell growth. However, the role that Jak2 plays in AT1-R-mediated vascular cell growth and remodeling in vivo is less clear. We hypothesized that in vivo, Jak2 plays a rate-limiting role in Ang II-mediated neointima formation following vascular injury. Using the Cre-loxP system, we conditionally ablated Jak2 from the VSMC of mice. We found that these mice are protected from Ang II-mediated neointima formation following iron chloride-induced vascular injury. In addition, the VSMC Jak2 null mice were protected from injury-induced vascular fibrosis and the pathological loss of the contractile marker, smooth muscle α-actin. Finally, when compared to controls, the VSMC Jak2 null mice exhibited significantly less Ang II-induced VSMC proliferation and migration in vitro and in vivo and more apoptosis. These results suggest that Jak2 plays a central role in the causation of Ang II-induced neointima formation following vascular injury and may provide a novel target for the prevention of neointima formation. © 2011 Elsevier Ltd