Our studies indicate that Bcr Abl  Elesclomol HSP-90 inhibitor alone does not lead to Jak2 activation, as addition of the IL 3 receptor is required.18 It is of interest that the Jak2 kinase seems to be involved in phosphorylation of Tyr 360 of Bcr Abl. Our studies with Bcr serine kinase indicate that Tyr 360 is a critical regulator of Bcr serine/threonine kinase activity,32,33 and that phosphorylation of Tyr360 of Bcr downregulates its serine/threonine kinase activity.32,33 Bcr resembles kinases such as pyruvate kinase, which is known to require a free tyrosine residue to maintain its kinase activity.34 The fact that Y177F mutant of Bcr Abl is similar to wild type Bcr Abl in response to Jak2 inhibition, suggests that Tyr177 is one of several possible Jak2 phosphorylation sites in Bcr Abl necessary to maintain functional Bcr Abl levels.
Transmission of downstream signals induced by IL 3 may be enhanced by Jak1 interaction with Jak2.30 In this regard, we found that a putative pan Jak kinase inhibitor appeared to be more potent in reducing levels of Bcr Abl and reducing levels of pTyr177 in Bcr Ablt cells compared with the selective Jak2 kinase inhibitor.35 We note that WP1193, despite its considerably less in vitro potency for phosphorylating Tyr177 in kinase assays compared with TG, still maintained similar or greater potency to reduce Jak2 effects in intact cells expressing Bcr Abl. It is possible that WP1193,s greater in vivo potency may be because of its ability to inhibit Jak1 as well Jak2 inside Bcr Ablt cells, although other explanations are possible.
Because of the apparent increased overall potency of WP1193 compared with TG101209, we chose to test WP1193 for its effects on inhibition of Bcr Abl,s oncogenic effects in mouse tumor models. The results indicate that WP1193 was a potent inhibitor of solid tumor formation induced by CML line K562 R and a strong inhibitor of oncogenic effects of IM resistant T315I in nude mice. Moreover, WP1193 had no observable toxic effects on mice injected with WP1193 only over a 2 week period. Importantly, Jak2 inhibition was effective in apoptosis induction in IM resistant blast crisis cells, IM resistant accelerated phase cells, IM resistant chronic phase and CD34t progenitors from accelerated and blast crisis patients.
We conclude from these experiments that Jak2 is the main tyrosine kinase that controls signaling in Bcr Ablt cells, as Jak2 appears to use the Bcr Abl protein as a platform to activate the Ras and PI 3 kinase pathways by phosphorylating Tyr 177 within the Bcr portion of Bcr Abl. Jak2 inhibition also strongly reduced STAT5 tyrosine phosphorylation, possibly because Jak2 inhibition may reduce functional Bcr Abl levels. A model summarizes our current and past findings on Jak2 functions in Bcr Ablt leukemia. Importantly, leukemia cells expressing either IM resistant forms of Bcr Abl or having other forms of drug resistance undergo apoptosis on exposure to Jak2 inhibitors20,21, suggesting that Jak2 inhibitors have potential for treatment of drug resistant CML. BCR ABL plays an essential role in the pathogenesis of chronic myeloid leukemia and some cases of acute lymphocytic leukemia. Even though ABL kinase inhibitors have shown great promise in t