Function And Mechanism Of PI3K/AKT Signaling Pathway In Pediatric T-Cell Acute Lymphoblastic Leukemia

Background: The PI3K/Akt signaling pathway plays a central role in cell growth,proliferation and survival in physiological conditions.This signal pathway is considered to be an innovative targeted therapy of cancer,and its abnormal activation has been proved to be related to T-cell acute lymphoblastic leukemia(T-ALL).Despite improved treatment strategies,such as multi-drug combination,high-dose chemotherapy and all kinds of application and popularization of hematopoietic stem cell transplantation,children with drug resistance or relapse T-ALL are still rather worse and its overall outcome and prognosis are much poorer than the more common B-lineage ALL.Objective: To explore the relationship between the PI3K/Akt pathway and the pediatric T-ALL,so as to probe the exact molecular mechanisms of T-ALL and provide more directions for its treatment.Method: 7 cases of new or recurrent acute T lymphocyte leukemia children with clinical information were collected in the children's hospital affiliated to the capital institute of pediatrics from Dec.2015 to Dec.2016,with 7 age and gender matched healty children as control(All was informed consent).The expressions of key genes in PI3 K pathway were analyzed by western blot RT-PCR analysis,the PI3 K enzyme activities were detected by ELISA,and the CCRF-CEM's proliferation and its apoptosis were tested by MTT and flow cytometry technology on T-ALL cell lines CCRF-CEM in different treatment group.Results: The results of T-ALL children in clinical showed that PI3 Kprotein and gene expression level were higher apparent than the control group(P<0.05),and PI3 K enzyme activity increased as well(P<0.05);PI3K inhibitor LY294002 made a significant inhibition of cell proliferation and promoted cell apoptosis.LY294002 also enhanced the effectiveness of clinical commonly used chemotherapeutic drug DNR.In combination LY294002 and DNR treatment group cell viability dramatically declined,apoptosis and the apoptosis relation protein Casepase3 expression in T-ALL patients was obviously higher than the control and the single drug group;PI3K/Akt signaling pathway related proteins and gene expression level,PI3 K,Akt,GSK3? transcription in CCRF-CEM were significantly higher than the control(P< 0.05),while PTEN transcription was significantly lower than the control(P<0.05).Conclusions: The abnormal activation of PI3K/Akt signaling pathway might play an important role in pediatric T-ALL patients,especially in the cell proliferation or apoptosis.The results might provide new train of thought and direction in targeted suppress this signal pathway or in combination with other chemotherapy drugs therapy in looking for the more effective and less cytotoxic treatment of pediatric T-ALL.