PD0325901 MEK inhibitor contributing to responses to BCR ABL

is by a JAK2 inhibitor. Collectively, these results indicate that activation of the JAK2 STAT5 pathway in CML stem/progenitors is likely to be an important mechanism PD0325901 MEK inhibitor contributing to responses to BCR ABL targeted therapies and identifi cation of Ahi 1/AHI 1 as a novel mediator involved in this pathway suggests AHI 1 alone or in combination with JAK2 and STAT5, as potential additional therapeutic targets. The most revealing result presented here is the fi nding that expression of BCR ABL was consistently associated with an up regulation of endogenous Ahi 1/AHI 1 transcripts and an increase in Ahi 1/AHI 1 protein expression in several overexpression and inducible experimental systems. Up regulated AHI 1 expression has been noted in K562 cells, a cell line derived from a patient with CML in blast crisis.
In particular, modulation of AHI 1 expression in K562 cells regulates BCR ABL and JAK2 STAT5 activities, as described above. Importantly, AHI 1 is highly deregulated in primary CML stem/progenitor cells where levels of BCR ABL transcripts are also highly elevated, suggesting that deregulated expression of BCR ABL and AHI 1 may be clinically relevant to BMS-536924 their cooperative activities that result in a permanently expanding clone of deregulated stem cells during leukemia development. Indeed, our study further demonstrates that highly elevated levels of AHI 1 in CML stem/progenitor cells from IM nonresponders and blast crisis patients correlate with their relative resistance to TKIs.
Similarly, a potential mechanism for a physical interaction between Ahi 1/AHI 1 and BCR ABL is revealed based on their molecular structures, which are compatible with specifi c protein protein interactions. Ahi 1 may interact with BCR ABL through its SH3 domain or its SH3 binding sites or through the SH2 domain of BCR ABL if Ahi 1 is tyrosine phosphorylated. In addition, Ahi 1 may bind to a SH2 containing protein that is a substrate of BCR ABL, thus forming a complex, as it is known that BCR ABL is extensively tyrosine phosphorylated, providing numerous, potential docking sites for SH2 domain containing proteins. Moreover, Ahi 1 may interact with multiple domains of BCR ABL, as demonstrated by other BCR ABL interacting proteins.
Although more detailed structural mapping will be required to defi ne specifi c protein protein interactions between Ahi 1 and BCR ABL, in association with JAK2, our fi ndings that coexpression of Ahi 1 in BCR ABL transduced cells can completely rescue IM induced suppression of cell growth in the presence of IL 3 suggests that Ahi 1 may not be a direct substrate of the BCRABL tyrosine kinase, but rather a modular protein that forms a stable protein interaction complex with other tyrosine phosphorylated proteins to mediate IL 3 dependent BCR ABL and JAK2 STAT5 activities. In addition, this protein interaction complex seems to be disrupted by suppression of tyrosine phosphorylation of BCR ABL by IM. Studies are underway to defi ne how AHI 1 specifi cally interacts with BCR ABL and JAK2. It was interesting to note that enhanced phosphorylation of Src was observed in Ahi 1 coexpressed BCR ABL inducible cells in the presence of IL 3, suggesting that other kinases are also activated with stimulation of IL 3 when BCR ABL and AHI 1 are coexpressed. 

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