Toaddress this, we evaluated the effect of a structurally distinct JAK2 Afatinib inhibitor with enhanced selectivity over these other Vorinostat HDAC inhibitor signaling molecules. At exposures that resulted incomparable efficacy to MRLB-11055, this inhibitor demonstrated identical reductions in lymphocyte populations. One explanation for these findings is that the reduction in these cell populations is due, at least in part, to inhibition of JAK2 itself, which is consistent with a role of JAK2-dependent cytokines such as IL-12 in lymphocyte development. We have demonstrated that intermittent dosing can attenuate many of 
the undesirable effects that will likely be associated with the use of JAK2 inhibitors in the treatment of MPD. In addition to signaling downstream of the EPO receptor, JAK2 plays a role in mediating signaling from a variety of molecules, including IFNc, IL-6, TPO, GM-CSF, prolactin, growth hormone, and angiotensin 1. The JAK2 inhibitor TG101348 has been described as a molecule that is both efficacious in a murine model of PV and sparing of T lymphocytes. While inhibition of pSTAT5 was clearly demonstrated 2 hours after TG101348 administration, it is not clear how prolonged target inhibition was during dosing. As TG101348 required 42 days of continuous treatment to achieve hematocrit reductionsof18%,itisreasonabletopresumethattargetengagement may have been lower relative to MRLB-11055 for a given dosing cycle. Thus the apparently unperturbed T lymphocyte populations maybe explained by a lower level of target engagement. The effect on NK cells, which responded most sensitively to MRLB-11055 inhibition, was not measured with TG101348. We have demonstrated that intermittent dosing of a JAK2 inhibitor can effectively normalize erythroid progenitor populations and thereby effectively treat conditions of polycythemia and splenomegaly in mouse models of PV. Our data can provide signficant guidance to the clinical development of JAK2 inhibitors. While the kinetics of erythropoesis are likely different in human disease, our data provide proof-of-concept for the use of erythroid progenitor populations as early biomarkers of target tissue efficacy, that could guide development of optimized intermittent dosing schemes to provide patients with improved therapy. Furthermore, our data show that lymphoid populations, in particular NK cells, serve as sensitive biomarkers for JAK inhibitor toxicity that is potentially mechanism-based. CD36 is a member of the scavenger receptor family with a broad cell type expression. The specificity of this receptor for oxidized lipoproteins is extensively documented. This receptor is up regulated by ox-LDL in macrophages and contributes to the formation and accumulation of foam cells at sites of arterial lesions during early and late atherosclerosis. This concept was validated by the finding that mice with double CD36 and ApoE deficiency exhibited a greater than 77% decrease in aorta lesions and 50% decrease in aortic sinus lesions despite the induction of a very high atherogenic milieu. This phenomenon was explained by the fact that recruitment and accumulation of foam cells at sites of lesions were considerably reduced in animals lacking CD36. Such a conclusion was however challenged by the observation that combined deficiencies in scavenger A and CD36 functions did not ameliorate atherosclerosis in hyperlipidemic mice. The role of CD36 in the binding and transport of long chain fatty acid in enterocytes and adipocytes is also well documented. The protein is involved in the control of the intestinal transit of cholesterol, triglycerides and fatty acids. CD36 deficiency can also rescue lipotoxic cardiomyopathy and control hepatic triglycerides storage and secretion.