STAT5 and AKT Signaling Pathways in Chronic Myeloid Leukemia
Introduction. Chronic myeloid leukemia (CML) is a chronic form of leukemia resulting from primarily myeloid lineage cells dividing and entering peripheral blood immaturely1. During disease progression, CML can result in altered blood platelet and WBC profiles while causing hepatosplenomegaly1,2. With a median diagnosis age of 672-4, most cases are associated with a Philadelphia chromosome (Ph1) where BCR-ABL1 fusion is created1,5,6. The auto-kinase activity of BCR-ABL1 involves phosphorylation of two crucial downstream proliferation signaling family proteins STAT55,7,8 and AKT6,8. Altered downstream effector protein function interferes with cellular apoptosis and proliferation8 thus resulting in the progression of three phases such as chronic phase (CP), accelerated phase (AP) and blast phase (BP) crisis1. Methods. To test viability of STAT5 inhibition, in vitro small hairpin RNA (shRNA) knockdown of STAT5 family was performed on K562, LAMA84 and MEG01 cell lines and apoptotic annexin V was gauged7. Viable CML CD34+ viable colonies were measured at presence of STAT5 knockdown7. Mice transplanted with CML with variation of either STAT5 or total deletion were tested for survival time after transplantation5. Abnormal cell cycle indicator P27 specifically at AKT signaling location measured in BCR-ABL1 colonies and in presence of AKT inhibitor were compared9. Hepatosplenomegaly disease burden was gauged in vivo using MK2206 AKT inhibitor at different dosages and measuring degree of hepatosplenomegaly6. Results. In vitro knockdown of STAT5 with shRNA increased detection of annexin V cells significantly7, particularly in shS5B and shS5A/B variations7. Similarly, inhibition of STAT5B significantly reduces CML CD34+ cell colonies7. In vivo deletion of STAT5 family significantly increased mice survival time period after transplantation5. In the presence of AKT inhibitor LY294002, cell cycle indicator P27 phosphorylation is reduced particularly at AKT site 157 suggesting reduced disease burden9. Another AKT specific inhibitor MK2206 reduces disease burden by reducing hepatosplenomegaly at dosage of 120 mpk especially in the liver suggesting inhibition of downstream effector proteins could be beneficial in treating CML6. Conclusion. Both in vivo and in vitro studies have found that downstream effector proteins of CML contribute significantly to disease progression in that the inhibition of AKT and STAT5 signaling pathways reduce disease burden8,10. By slowing the cellular disease transformation process, AKT and STAT5 inhibition could offer a distinct and specific target for treatment of CML. With specific targets, overall results show prominent inhibition of CML progression in various cell lines. The overall challenge lies in the dosage required to reach effector protein sites.
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