Recently, we have found that AQP5 expression in NIH3T3 cell line induces cell proliferation through the activation of Ras, suggesting an association between AQP5 and the Ras signal transduction pathway. In addition, we have reported that AQP5 triggers Ras/ERK/Rb pathway in HCT116 colon cancer cell line, thereby promoting cell proliferation. Furthermore, we have observed that AQP5 activates c-Src, and, thus, triggers cell invasion and epithelial-mesenchymal transition in BEAS- 2B human bronchial epithelial cell line. However, these finding were all based on solid tumors and the role of AQPs in the development of hematological malignancies are largely unknown. Thus, in this study, we have pursued the role of AQP5 in CML as a first model to study the role of AQPs in blood cancer. We report, for the first time, that AQP5 promotes cell proliferation in CML cell lines possibly through the activation of BCR-ABL1 and Akt. We have also found that AQP5 may prolong cell survival by inhibiting apoptosis via caspase 9 pathway. We believe that these findings may shed light in discovering novel molecular targets for CML treatment, where drug resistance has become a huge obstacle for oncologists. However, there needs to be further investigation into several other candidate cell signaling pathways important in CML progression that may be affected by AQP5. Our next plan is to examine changes in the signal transduction ICG-001 molecules related with the BCR-ABL1 pathway such as CrkL, Ras, Jak2, Stat5, and c-Myc as well as molecules that are not linked with BCR-ABL1 pathway including Lyn in both AQP5-overexpressing and AQP5- silenced CML cell lines. Also, we plan to delve into the details of the apoptosis pathways including Bcl-2, Bax, Bad, and Fas. Ultimately, our findings including proliferation assay and molecular expression assays await further validation with primary CML cells. One question that may arise is the identification of the adaptor molecule that directly interacts with AQP5 to exert its alleged effects in CML. One possibility is for AQP5 to interact with and, thus, activate Lyn in CML cells. With protein microarray and GST pull-down assay, we have reported that AQP5 binds to Lyn, the activation of which has been found to be one of the mechanisms of imatinib mesylate resistance. Bortezomib Similar to our findings, Lyn ablation led to enhanced apoptosis of CML cells, even in primary cells resistant to imatinib mesylate therapy. Although the pathway of Lyn activation seems to be independent of BCR-ABL1, it would be worthwhile to explore the possible interaction between Lyn and AQP5 in CML cells and see how AQP5 ablation affects the growth of imatinib mesylate-resistant primary CML cells. In addition, our recent studies suggest that Grb2 and c-Src, both of which showed in vitro and in vivo binding with AQP5, could be some of the candidate adaptor molecules which interact with AQP5 in CML cells. Thus, we plan on performing binding assays with the above candidate molecules in CML cell lines and primary CML cells.