Prognostic Significance And Mechanism Of Action Of CD58 Costimulatory Molecule In Acute Myeloid Leukemia

Objective: This study aims to investigate the different expression levels of costimulatory molecule CD58 in acute myeloid leukemia (AML) and its influence on the prognosis, and to study the mechanisms of action, so as to further improve the prognosis and risk stratification system of AML and guide the clinical treatment.Methods: This study included 138 patients diagnosed with primary AML(excluding M3)at the Department of Haematology, Chinese PLA General Hospital from January 2011 to December 2015, and they were divided into two groups according to the expression intensity of CD58: CD58+ and CD58-, the clinical-laboratorial characteristics and survival time of these two cohorts were retrospectively analyzed, and the effects of CD58 on prognosis were assessed by univariate and multivariate statistical analysis. For the mechanism research, CD58 monoclonal antibody (TS2/9) and CD58 si-RNA were performed on the U937 and Skno-1 cell lines to reduce CD58 expression(as CD58-). The cytotoxicity effect of NK cells on leukemia cells was proved by the cytotoxicity assay and the effect of CD58 on the doubling rate of tumor cells was confirmed by CCK-8 test in vitro. The doubling rate of intracorporal leukemia blasts with different expression levels of CD58 was analyzed by using flow cytometry to detect the minimal residual disease after the last consolidation and at recurrence, so as to further investigate the prognosis effect of CD58 in acute myeloid leukemia,which provided new theoretical basis for future clinical prognosis stratification and individualized treatment.Results: In terms of laboratorial and clinical characteristics, there was no difference in the count of blasts cells, white blood cells, platelet and hemoglobin between CD58+ and CD58- patients(P>0.05). However, the CD58- patients had an older median age of onset(49 vs 42 years, P=0.05) and a higher incidence of hyperleukocytosis(22.2% vs 5.9%, P=0.01)than that of CD58+ patients. Secondly, the constituent ratio of favorable karyotype(5.7%vs 29.6%), intermediate karyotype(80% vs 58.8%) and poor karyotype (14.3% vs 11.6%)were statistically different in the CD58- and CD58+ patients(P = 0.01).There was no difference in the remission-induced rate and the time from chemotherapy-induction to complete remission (CR) between the CD58- and CD58+patients(P> 0.05), but the CD58- patients had a worse 3-year EFS and 5-year OS than the CD58+patients (42.9% vs 53.1%, P=0.04; 33.5% vs 44.6%, P=0.003); Furthermore, the median recurrence time was earlier in the CD58- relapsed patients(10 vs 12.5 months,P=0.03). Multivariate analysis also demonstrated that CD58- was an independent poor prognostic factor(HR=1.9, P= 0.02). The survival time of patients receiving allogeneic hematopoietic stem cell transplantation(Allo-SCT) was significantly longer than the non-Allo-SCT patients in both groups(57% vs 14.2%, P=0.01; 54.2% vs 31.7%, P= 0.01).As for mechanism research, in the context of the effector-target ratio was 1: 1, 2:1 and 5:1,the cytotoxicity of NK cells was reduced by 4.6%, 7.3% and 8.3%(P < 0.05). When the CD58 gene was knockouted, the doubling rate of the experimental group was not statistically different from that of the control group at each time point (P> 0.05). For the relapsed patients, the median doubling rate of leukemia blasts was statistically different in the CD58- and CD58+ groups(14.7% vs 6.6%/month, P= 0.01).Conclutions : Compared with the CD58+ patients, CD58- patients have an older median age of onset, higher incidence of hyperleukocytosis, less favorable karyotype, and are more liable to early recurrence and death. Multivariate analysis confirmed that CD58-immunophenotype is a poor prognostic factor, and the high-risk characteristic could be reversed by Allo-SCT. In vitro experiments, the killing effect of NK cells on the CD58-cell lines is weaker than that of CD58+ cell lines; The decreased expression of CD58 by gene silencing does not alter the doubling rate of leukemia cells. The CD58- relapsed patients have a faster doubling rate than that of CD58+ patients. In summary, this study suggests that poor prognosis of CD58- AML patients may be due to immune escape of leukemia cells by reducing the expression of CD58.