A Preliminary Study On The Role And Mechanism Of Demethylation Drugs In CML-blast Crisis

Objective During the era of Tyrosine kinase inhibitor(TKI),the incidence of disease progression of chronic myeloid leukemia(CML)has been greatly reduced,but it is still unavoidable,and there are still patients who are first diagnosed as the BC.The treatment response,overall survival,and prognosis of patients in BC especially in lymphoid blast crisis are frustrating.It is also difficult to unify the recommended treatment regimens for these patients,and the combined treatment regimens seem to have better results.It has been reported that changes in epigenetic regulation play an important role in disease progression of CML,of which deoxyribonucleic acid(DNA)hyper-methylation is the most common one.This study starts with the analysis of clinical cases,hoping to find guidance for a unified treatment plan for patients in BC,and some new regimens for combination treatment.The analysis of DNA methylation can help us understand more about the pathology of CML and epigenetic regulation in disease progression so that we find more targets and have more drug options in treatment.Methods We conducted a retrospective study in which the clinical characteristics of23 patients with blast crisis were analyzed,and the treatment plan,response rate and survival time of 10 patients with relatively complete clinical data were further analyzed.In vitro,the biological effects of Decitabine plus TKIs in K562 cells was observed through the assay of cell proliferation,apoptosis,cell cycle,and colony formation.At the same time,genome-wide methylation detection was performed in 6patients of CML in different phases by EPIC methylation chip technology.Results As the first-line inducing treatment for patients in lymphoblastic crisis,VP(vindesine plus prednisone)combined with TKI has a CHR rate of 60% and an MMR rate of 40%,but the relapse rate is 100% excluding one patient undergoing allo-HSCT.Patients who relapsed could reach CHR again but cannot reach MMR;the rate of CHR in patients with mutations in ABL kinase domain was 80% higher than that of the negative group.The demethylation drug was effective in refractory patients.Decitabine combined with the second-generation TKI has a synergistic effect on inhibiting cell proliferation,colony formation,and inducing apoptosis of k562 cells in a concentration-dependent and time-dependent manner,while the combination effect with the first-generation TKI is not good.The DNA of patients in different phases has significantly different methylation sites and regions,and patients in lymphoblastic crisis show hypermethylation in some regions.The genes associated with these regions are related to PI3K-akt,MPAK,Rap1,TCR,FAK and other signal pathways.Conclusions VP combined with TKI can be the first-line recommended treatment for patients of CML in lymphoblastic crisis.Patients who are able to take allo-HSCT should be transplanted as soon as possible;high relapse rates and refractory issues are still big challenges.Demethylation drugs were effective in patients with refractory lymphoid blast crisis,while those with negative ABL kinase domain mutations were even worse,suggesting that epigenetic regulation also plays an important role in disease progression.The change of DNA methylation is complex during the progression,and other new treatments are urgently needed on the basis of demethylation.Therefore,the epigenetic regulation mechanism of disease progression needs to be further studied to find more effective targets and improve the prognosis of patients in CML BC.