our studies demonstrate that PI-103 PI3K is also physically associated with JAK2

Finding also explains the observation that CML progenitor cells with suppression of AHI 1 experienced greater inhibition of CFC generation in response to dasatinib, a more potent TKI that also inhibits Src activity. In conclusion, our studies demonstrate that Ahi 1/AHI PI-103 PI3K inhibitor 1 is a novel BCR ABL interacting protein that is also physically associated with JAK2. This AHI 1 BCR ABL AK2 complex seems to modulate BCR ABL transforming activity and TKI response/resistance of CML stem/progenitor cells through the IL 3 dependent BCR ABL and JAK2 STAT5 pathway. These results suggest that a more promising potential therapeutic approach would be the combined suppression of BCRABL tyrosine kinase activity, Ahi 1/AHI 1 expression, and JAK2 STAT5 signaling.
Our previous experiments suggest that Janus kinase 2 has an important role in Bcr Ablt cells, and that Bcr Abl expression leads to activation of Jak2.1 3 Bcr Abl is known to drive the Grb2 Ras Raf Mek1/2 Erk pathway and the PI 3 kinase pathway involving Gab2,4 6 the Jak2 STAT3 BMS 777607 pathway7,8 and the Bcr Abl STAT5 pathway.9,10 Phosphorylation of Tyr 177 Bcr Abl is a critical event required for development of chronic myeloid leukemia, as the Y177F mutant of Bcr Abl diminishes CML disease.4,11,12 pTyr177 binds Grb2 leading to Grb2 SOS complex formation and activation of the Ras pathway. Continuous treatment with IM induces IM resistance because of a number of events including mutations in the tyrosine kinase domain,13 amplification of the Bcr Abl gene14,15 and a Bcr Abl independent mechanism involving Lyn kinase.
16,17 All these events lead to poor responses to IM therapy, allowing progression of the disease. Jak2 activation in Bcr Ablt cells appears not to involve phosphorylation of Jak2 by the Bcr Abl tyrosine kinase but the interaction of Bcr Abl with the IL 3 receptor chains, specifically the b chain of the receptor.18,19 The Bcr Abl/Jak2 signaling pathway appears to be housed in a highmolecular weight structure called the Bcr Abl network complex. 20 22 Importantly, Jak2 kinase inhibition overcomes IM resistance by inducing apoptosis in IM resistant cell lines and also cells from CML patients at the blast crisis stage.20,21 Residual CML disease appears to involve primitive progenitor cells, which have been shown to be present in niches in the bone marrow.23,24 These cells are considered quiescent and not Bcr Abl dependent.
25 27 These findings require a search for new therapeutic targets and compounds to eradicate these tyrosine kinase inhibitors resistant cells from the bone marrow niche. Jak2 is an important signaling component in hematopoietic cells, as it transmits signals generated by interaction of cytokines such as IL 3 with the IL 3 receptor. The a and b chains of the IL 3 receptor are part of a large dodecamer structure in which two Jak2 molecules are bound to the b chain in close proximity to each other.28 Jak2, as a result of interaction of IL 3 with the IL 3 receptor, becomes activated by autophosphorylation at Tyr 1007.28,29 Studies by Huang et al.30 suggest that IL 3 signaling driven by activated Jak2 is enhanced by Jak1 interaction with Jak2. Our new findings indicate that Jak2 controls Bcr Abl signaling in CML cells, as either Jak2 knockdown or Jak2 inhibition drastically reduced the levels of

Leave a Reply

Your email address will not be published. Required fields are marked *

*

You may use these HTML tags and attributes: <a href="" title=""> <abbr title=""> <acronym title=""> <b> <blockquote cite=""> <cite> <code> <del datetime=""> <em> <i> <q cite=""> <strike> <strong>