The Lyn Kinase In Imatinib-resistance Chronic Myelogenous Leakemia

Background and Objective:Chronic myelogenous leakemia (CML) is a malignant tumor which is composed of clonal preliferation of hematopoietic stem cell and is found in15%-20%of patients with leakemia.Imatinib is a protein tyrosine kinase competitive inhibitor of BCR/ABL fusion gene, this agent has proven highly effective in patients with CML.And now, imatinib has been recommended as the first line thrapy for CML in NCCN.Although imatinib is effective for CML, part of patients become imatinib-resistant in early or the course of treatment.The resistant mechanism of imatinib may be various, but now, resistance to imatinib from BCR/ABL gene amplification, leading to overexpression of BCR/ABL protein, or point mutations in the BCR/ABL gene are deemed to be the most important mechanism of imatinib-resistant. However, sevaral researchs on imatinib-resistant K562cell lines found that:they did not discover BCR/ABL gene amplification, leading to overexpression of BCR/ABL protein, or point mutations in the BCR/ABL gene in these imatinib-resistant K562cell lines, on the contrary, they found the high level of Lyn which was one major member of SFK family.Therefore, this study test the expression of Lyn in76CML patients with clinical characteristics, clinical effect and chromosome abnomality to explore the significance of Lyn in imatinib-resustant CML.Methods:Western blotting was used to observe the expression of Lyn in bone marrow mononuclear cells of76patients with CML and10normal human being.Gene expression of BCR/ABL was detected by real-time PCR.Cytogenetic data were obtained from10of them by R band karyotypic analtysis.Using the data SPSS17.0statistical software t test (or nonparametric test)、Spearman rank correlation (or Pearson correlation), P<0.05showed a statistically significant.Results:1、Lyn and imatinib-resistant Lyn expression in imatinib-resistant patients was significantly higher than normal human being、 newly diagnosed patients and effective patients (P=0.0025、P=0.0014、 P=0.0001).However, there was no statistically significant difference between newly diagnosed patients、effective patientsnormal and human being (P=0.310、P=0.2355)2、BCR/ABL gene quantitative analysis We detected the expreession of BCR/ABL gene in newly diagnosed patients、effective patients and imatinib-resistant patients, the results showed that BCR/ABL expression in imatinib-resistant patients and newly diagnosed patientswas was significantly higher than effective patients (P=0.035、 P=0.026)3、Lyn and BCR/ABL gene Correlation between Lyn and BCR/ABL was analyzed, there was no obvious relation between Lyn and BCR/ABL (P=0.2780)4、Lyn and clinical characteristic All the CML patients and normal human being expreessed Lyn.There was no significant relationship with median age, gender, median hemoglobin, and median platets level, percentage of peripheral blasts, size of spleen (P=0.07、 P=0.068、P=0.869、P=0.968、P=0.873、P=0.647).The Lyn expression of the mean leucocyte above100×109/L at the first visit was obviously higher (P=0.0465)5、Lyn and chromosomes There was1case with chromosome abnormality in t (6;22) and t (2;9) in10imatinib-resistsnt CML patients, coexisting with Ph chromosome.The rest of9cases only existed Ph chromosome.There was no relationship between Ph chromosome and other clonal chromosome abnormality except Ph chromosome (P=0.487)Conclutions:1、CML and normal human being all expressed Lyn.2、Lyn was overexpressed in imatinib-resistant CML.3、There was no obvious relation with median age, gender, median hemoglobin, and median platets level, percentage of peripheral blasts, size of spleen.The increased Lyn expression had closely relationship with WBC count level.4、There was no correlation between Lyn and BCR/ABL.5、Lyn was not relevant to karyotype.