LY2608204 inhibitor showed a statistically significant increase in white blood cell

However, bortezomib treated BCR ABL transduced mice had fewer leukocytes, resembling vector control mice. Similarly, the complete blood count showed a statistically significant increase in white blood cell count among the  LY2608204 inhibitor transduced mice compared to vehicle only control or BCR ABL mice treated with bortezomib. The normal reference range at the laboratory tested is 5.4 16?103 cells/l. Yet another significant symptom of CML like disease in this model is splenomegaly, and by 21 days post BMT, we clearly observed splenomegaly in vehicle treated BCR ABLtransduced mice, but not in vector control mice. Bortezomib treatment significantly reduced splenomegaly in BCR ABL transduced mice by day 21 and resulted in further reduction by day 42. Upon examination of the spleen tissue by hematoxylin and eosin staining, we found that spleen samples from BCR ABL mice treated with vehicle control displayed heavy infiltration of myeloid cells.
In contrast, bortezomibtreated BCR ABL spleen samples showed little myeloid infiltration. We also observed similar pathological changes in the liver. We next determined whether the attenuation of CML like pathophysiology in the BCR ABLinduced CML mouse model correlated with increased survival. BCR ABL transduced mice treated with vehicle control began to die as early as 16 days after BMT, but the majority of mice in this group died during the third and the fourth weeks after BMT. In the bortezomib treated BCR ABL group, 47% of the mice had survived at the end of one month after BMT, and the last mouse in this group died by day 49 after BMT. These data show that the survival of bortezomib treated, BCR ABLtransduced mice was significantly prolonged.
Finally, we determined that bortezomib treatment did result in a molecular regression of leukemia, as qRT PCR analysis of BM cells on Day 21 revealed that the normalized copy number of BCR ABL in bortezomib treated mice was significantly reduced compared to that of an untreated mouse. Bortezomib treatment of BCR ABL transduced leukemic mice restores normal expression of FoxO3a and its targets TRAIL and BIM We analyzed the effect of bortezomib treatment on FoxO, TRAIL and Bim expression. We could barely detect FoxO3a protein in the BCR ABL transduced mice, whereas moderate expression was found in control mice, providing further support for inhibition of FoxO3a tumor suppressor by the BCR ABL oncogene.
The positive staining of myeloperoxidase in vehicle treated BCR ABL mice confirmed that overall protein expression was not affected in these mice. Bortezomib treatment completely restored FoxO3a protein expression to a level comparable in vehicle treated control mice. We observed similar results in the marrow where FoxO3a protein expression was virtually absent in vehicletreated BCR ABL transduced mice but was restored in response to treatment with bortezomib. Taken together, these results provide novel in vivo evidence that greatly diminished protein expression of FoxO3a tumor suppressor is associated with BCR ABL mediated leukemogenesis. Given that the phosphorylation of FoxO3a is an important mechanism for its negative regulation, we compared FoxO3a phosphorylation in control and BCRABL transduced mice, using an antibody that detects the phosphorylated forms of FoxO3a as well as that of the FoxO family member FoxO1. 

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>