Expression Of ABCA3 And P-gp In Acute Leukemia And Their Clinical Significances

BACK GROUND The treatment of Acute leukemia (AL) has gained many advanced development during these years, however, multidrug resistance (MDR) decreases the curative effect of chemotherapy drastically. ATP-binding cassette transporter (ABC transporters) superfamily members play an important role in multidrug resistance, the evidences include P-glycoprotei (P-gp), multidrug resistance-associated proteinl (MRP1) and breast cancer resistance protein (BCRP). During recent years, a new ABC transporter superfamily member related to MDR of AL-ABCA3 had been discovered. It located on Intracellular Membranes, and it was supposed that ABA3 mediated clinically relevant MDR by drug sequestration in late organelles of the endosomal system which was different to MDR mechanism mediated by P-gp. How ever, little has been known about ABA3 until now.OBJECTIVE To investigate the expression of ATP-binding cassette transporter A3 (ABCA3) and P-glycoprotein (P-gp) gene in acute leukemia (AL) and to explore the role of these two genes in multidrug resistance and their clinical significance.METHODS1. Bone marrow mononuclear cells from 42 newly diagnosed,21 relapse/ refractory AL (including AML and ALL) patients and 10 normal controls were analyzed, Reverse transcription polymerase chain reaction (RT-PCR) was used to detect the expressions of ABCA3 and P-gp mRNA.2. One-factor analysis of variance was used to analyze the expression pattern of ABCA3\P-gp mRNA in different groups. 3. Pearson correlation coefficient was used to analyze the relevance between ABCA3 and P-gp.4. According to their response of chemotherapy, the newly diagnosed AML patients was divided into two groups:complete remission group (CR) and non-complete remission group (PR+NR), levels of ABCA3\P-gp mRNA expression between the two groups were compared by T-Test, respectively.5. One-factor analysis of variance was used to analyze the expression pattern of ABCA3\P-gp mRNA in different subtypes of AML.6. Spearman correlation coefficient was used to analyze the relevance of ABCA3\P-gp expression and clinical variables (including the initial number of WBC, immunophenotype, blood platelet count, hemoglobin content, immunophenotype, chromosome karyotype and age); Using T-Test to compare ABCA3\P-gp mRNA expression between different gender.RESULTS1. The levels of ABC A3 and P-gp gene expression in the newly diagnosed AL group were higher than them in normal controls (P<0.01), and were higher in the relapse/refractory AL group than them in the newly diagnosed (P<0.01). Both of these two gene's expression levels in lymphocytic leukemia (ALL) groups were higher than them in the acute myeloid leukemia (AML) groups (P<0.05).2. The expressions of ABCA3 and P-gp gene were closely correlated (r=0.599, P <0.01).3. Compared to non-complete remission group, the complete remission group had lower expressions of ABCA3 and P-gp gene.4. The levels of ABCA3 expression in chronic myeloid leukemia (CML)-blastic phase were higher than that in other subtypes of AML (P<0.05, except M3), and were higher in M3 than that in M1 (P<0.05).5. The levels of P-gp gene expression had no difference between various subtypes of AML (P<0.05).6. The expressions of ABCA3 and P-gp gene had no relationship with the initial number of WBC, immunophenotype, blood platelet count, hemoglobin content, immunophenotype, chromosome karyotype, age and gender, (P>0.05).CONCLUSIONS1. Compared to normal controls, the AL patients had higher level of expressions of ABCA3 and P-gp gene; The Al patients, which had high level of ABCA3\P-gp expression, had poor drug sensitivity and more apt to relapse.2. The expressions of ABCA3 as well as P-gp were related to the multidrug resistance of AL cells, and these two genes were positively correlated.3. The two gene's expression levels in ALL group were higher than in AML group, which might provide explain to the causes of lower remission rates and higher relapse rates in ALL patients.4. Over-expression of ABCA3 and P-gp may lead to poor remission rate of AL pations; These two genes were important factors in poor therapeutic effect and unfavourable prognosis.5. The levels of P-gp expression had no differences between various subtypes of AML. The levels of ABCA3 expression in CML-blastic phase were higher than that in other subtypes of AML, which was consistent with the fact that CML-blastic phase patients easily created drug resistance and had lowe remission rate. AML-M3 patients had high levels of ABCA3 expression, which was incompatible with the fact that AML-M3 patients were easily to be induced remission by RA, prompting that ABCA3 had nothing to do with the resistance of RA in M3 patients.6. The expressions of ABCA3 and P-gp gene had no relationship with the initial number of WBC, immunophenotype, blood platelet count, hemoglobin content, immunophenotype, chromosome karyotype, age and gender, which demonstrate ABCA3\P-gp may be predictors independent these clinical variables.