The Expression Of ?-TrCP In Acute Myeloid Leukemia And The Roles Of F-box Proteins In Blood Malignancies

PARI ?The Expression of ?-TrCP in acute myeloid leukemiaBackground:Acute myeloid leukemia(AML)is a malignant disease with the proliferation of immature myeloid cells.The long-term survival of patients with hematologic malignancies is still unoptimistic because of the drug-resistance and relapse of AML.Recent studies suggest that ubiquitin proteasome system(UPS)mediated protein degradation of oncogenic proteins or tumor suppressor proteins plays a vital role in pathogenesis and progression of hematologic cancers.The ubiquitin proteasome system(UPS)is an conserved mechanism for protein degradation,including several procedures observed in protein ubiquitination.Firstly,ubiquitin is activated by the El enzyme,shifting to ubiquitin-conjugated enzyme E2 and combining with the targeted protein via ubiquitin-protein ligases(E3 enzyme).Finally,26S protease is responsible for is recognizing and degrading the ubiquitinated protein.The SCF(Skp1/Cul1/F-box)complex is one of major members of E3 ligases,which is composed of the scaffold protein Cullin1,the RING finger and protein Rbx1.Rbxl functions to recruit the E2 enzyme,and the adaptor protein Skp1(S phase kinase associated protein 1)acts to connect to F-box proteins that mediates recognition and recruitment of substrate.Recently,a large number of F-box protein family members have been identified to participate in the progression of hematological malignancies.?-TrCP belongs to the FBXW family,which is a sub-family of F-box proteins.?-TrCP plays an important role in various signaling pathways that are significant for tumorigenesis and seems to be an oncogene in hematologic malignancies.For example,P-TrCP controls H3K27 trimethylation activity through targeting EZH2 for degradation and mediates both NF-?B and wnt signaling pathways,which plays a vital role in the pathogenesis of lymphoma and Multiple Myeloma(MM).However,little research has been conducted on the effects of ?-TrCP in AML up to now.We investigate the expression of ?-TrCP in bone marrow of acute myeloid leukemia in order to explore the effect of ?-TrCP in the AML.Objective:This study aims to investigate the expression of ?-TrCP in bone marrow of AML by real-time fluorescent quantitative PCR and then analyze the correlation between ?-TrCP and the clinical properties of AML patients.Methods:We collected specimens of 100 patients with new diagnosed AML including 21 cases of M3 patients and 79 cases of non-M3 patents.Besides,we also collected 10 cases of relapsed AML(non-M3)patients and 24 cases of healthy donors.Then,we separate bone marrow mononuclear cells(BMNCs)and the total RNA was extracted from BMNCs.We detect the mRNA expression levels of ?-TrCP by real-time quantitative PCR,and to calculate the relative expression values of ?-TrCP.Lastly,the correlation between the expression of ?-TrCP and clinical features was analyzed,P<0.05 was considered statistically significant.Results:1.The relative expression level of ?-TrCP in bone marrow of new diagnosed AML and was higher than that in control group(P<0.05).However,the difference between the favorable M3 and healthy donors is not significant(P>0.05).2.The relative expression of p-TrCP in 6 cases of acute leukemia patients diagnosed newly was significantly higher than after treatment(P<0.05).3.79 cases of AML(non M3)patients were devided into two groups according to the expression of expression of P-TrCP.We found that high expression of ?-TrCP is related to the higher white blood cells(WBC)in peripheral blood and poorer karyotype.Besides,poorer OS and RFS is related to the higher P-TrCP expression(P<0.05).4.COX analysis showed the prognosis of AML(non M3)is related to many factors,including?-TrCP expression,age,WBC,PLT and BM blasts according to our research(P<0.05).Conclusion:1.We found that the overexpression of ?-TrCP in newly diagnosed and recurrent AML(non M3)patients.The relative expression of ?-TrCP of acute leukemia patients diagnosed newly was significantly higher than after treatment 2.The higher expression of ?-TrCP is related to the higher WBC in per:ipheral blood and poorer karyotype.Besides,higher expression of ?-TrCP is related to the poorer OS and RFS.Further study showed that p-TrCP expression was the independent risk factor of AML(non M3).PART ?The roles of F-box proteins in blood malignanciesUPS(Ubiquitin Proteasome System),a precise degradation system,mediates post-tanslational modification by a series of processes of protein ubiquitination.F-box protein is a vital role that takes part in protein ubiquitination and regulates several cellular physiological activities including cycle control,transcription,cell signaling,cell death,as well as DNA repair and DNA replication.Recently,a large number members of F-box protein family have been documented to be essential parts in the pathogenesis,development and drug resistance of malignancies.In this review,we will highlight the roles of the F-box in the development and drug resistance of the hematologic malignancies.