| Background and PurposeChronic myeloid leukemia (chronic myeloid leukemia, CML), a hematopoietic stem cell clone proliferative diseases, more than90%of patients with bone marrow cells in the presence of the Ph chromosome and BCR/ABL fusion gene, the global annual incidence of approximately1/10, OOOpopulation, accounting for about15%of adult leukemia-20%, the peak incidence between50-60years old, with a median survival of3-4years. It occurs mainly caused by the t (9;22)(q34; q11) gene transfer. The Ph chromosome encoding synthetic fusion gene BCR-ABL. In CML, P210BCR-ABL can activate several tyrosine kinase family of receptor signaling pathway, can play a series of chain reactions so that CML cells a proliferative advantage and the ability of anti-apoptotic. CML different stages of the disease, its clinical manifestations as well as its biological behavior of the tumor cells, treatment and prognosis are very different. Before targeted therapy drugs used in clinical, most patients with CML in chronic phase typically lasts about3-5years, many patients enter into the accelerated period of4-6months after the disease end-stage blastic phase. In the initial stages of treatment of CML patients, we use more traditional regimens to hydroxyurea, alpha-interferon and chemotherapy, radiotherapy spleen predominating. However, these so-called traditional treatment programs, poor efficacy, side effects, lower CML in clinical genetics or molecular remission. Before the discovery and application in the tyrosine kinase inhibitor (TKI), allogeneic hematopoietic stem cell transplantation as expected the only way to cure CML. However, due to the risk of death of allogeneic hematopoietic stem cell transplantation, it can not fundamentally improve CML treatment effects and long-term survival situation. TKI has been found for the P210protein targeted drugs change the treatment of CML major breakthrough. Its specific pathogenic mechanisms and the advantages of low toxicity, it is even more gratifying is that to TKI with any killing effect on normal cells. Imatinib (IM) is a tyrosine kinase inhibitors (TKIs) as a treatment for chronic myeloid leukemia cure for a wide range of in clinical applications. However, drug resistance often occurs at all stages of CML patients. Imatinib Nigerian drug resistance has plagued the majority of clinicians and patients, stage of resistance mechanisms are still unclear.Axl is one of encoding the receptor tyrosine kinase gene. By O’bryan such as in1991found in the DNA of human chronic myelogenous leukemia the tyrosine kinase Tyro3(also known as Rse, Sky, Brt, Dtk Etk2or Tif) AXL (aka Ufo, Ark or the tyro7) and Mer (aka Nyk, Eyk or Tyro12) together form a receptor tyrosine kinase subfamily (TAM family) and its nucleotide sequence has a high homology (28%to36%), with a similar molecular structure, by the extracellular region, intracellular and transmembrane domain3parts.Axl is the size of approximately140kD (1D=1u) transmembrane molecules, targeted at19q13. A total length of42185kb,698adenine and972cytosine, of931guanine and626thymine constitute20exons.In recent years, the proto-oncogene Axl has become one of the hotspots have been found in a variety of tumors, including breast cancer, prostate cancer, liver cancer, esophageal cancer, thyroid cancer, pancreatic cancer, malignant melanoma, Axl expression of thesetumor diagnosis, prognosis and treatment targeting molecules used in clinical work is closely related to the latest study found that can be used as diagnostic indicators of the effectiveness of the new targeted molecular drugs. The AXL excessive is a common feature of many cancer cells. And then some studies found that continuing high levels of Axl gastrointestinal stromal tumors mesylate imatinib imatinib resistance. Primary drug resistance in acute leukemia chemotherapy, there are also over-expression of Axl, and in some solid tumors resistant cases, we also found that the increase of Axl. Therefore, this study of59patients with chronic myelogenous leukemia patients Axl expression levels in bone manow mononuclear cells in the monitoring, analysis with clinical features, clinical efficacy, and thus to explore the AXL in imatinib-resistant CMLthe role of expectations imatinib the Nepal resistant CML treatment to provide some direction, so that the expression of these genes can be used to guide TKI in clinical and prognostic evaluation indicators. Methods1. An object of study:59adult patients with CML untreated patients from our department of hospitalized patients, aged17-65years old in all cases diagnosis blood disease diagnosis and treatment standards’3March2009-2012May’diagnostic criteria. Of which20were previously untreated patients diagnosed with chronic myeloid leukemia.39cases of patients were imatinib therapy than three months, according to its therapeutic effect, were included in the effective group therapy and treatment failure group. Effective treatment group32cases,7cases of treatment failure.12cases in the control group selected from the group consisting of non-bone marrow of patients with hematologic malignancies. Respectively monitoring their bone marrow cells in the expression level of the AxlmRNA.2. RNA extraction and reverse transcription:RT-PCR assay expression levels AxlmRNA:extracting bone marrow specimens of inpatients after mononuclear cells, total cellular RNA was extracted using Trizol method and test its quality and concentration, reverse transcription into cDNA, PCR amplification,agarose gel electrophoresis, the agarose gel is placed the gel imaging scanner in ultraviolet imaging, gel image analysis system to observe, analyze experimental results and photographed.3. Statistical analysis:Using statistical software SPSS17.0, quantitative real-time information belonging to the non-normality of measurement data, data with a median and quartiles CML patients with the IM treatment failure group, the treatment of the expression level of the effective group and the control group AxlmRNAcompared using Kruskal-wallis test again, the difference was statistically significant between the two groups among groups, the two groups were compared using the Mann-Whitney U test.P<0.05was considered statistically significant.Result1. The expression level of CML patients Axl mRNA is0.7269(0.3562-25.4722. The expression level of Axl mRNA in control group is0.2821(0.1901-0.5926).2. Imatinib treatment group Axl mRNA expression was0.6756(0.3441-21.6161), failure of imatinib treatment group, Axl mRNA expression was25.4722(0.4541-33.1631). Imatinib treatment failure was significantly higher than the control group, P=0.0001difference was statistically significant. Imatinib treatment failure was significantly higher than CML untreated group, P=0.0014difference was statistically significant. Imatinib treatment failure was significantly higher than imatinib effective group, P=0.0025difference was statistically significant.3. CML untreatment group compared with the control group, P=0.310difference was not statistically significant. Imatinib treatment is effective compared with the control group, P=0.2355difference was not statistically significant.4.59cases of chronic myeloid cell leukemia patients are expression of Axl, Axl expression with patients age (P=0.069), gender (P=0.070), the average hemoglobin level (P=0.868), average platelet count (P=0.964), outside the weekthe proportion of blood naive cells (P=0.911, spleen size (P=0.710), no significant correlation. White blood cell count is characteristic of CML CML patients the initial diagnosis, white blood cell count>100x109/L as the boundary divided into two groups and found that newly diagnosed CML white blood cell count>100x109/L group Axl expression was significantly increased (P=0.0395), the difference was statistically significant.Conclusion1. CML patients and normal persons express Axl mRNA.2. Axl mRNA expression levels of treatment failure group than the treatment group, suggesting that Axl may be related to the occurrence IM treat drug-resistant CML patients.3. AXL expression with gender, age, mean hemoglobin level, mean platelet count, the proportion of immature cells in peripheral blood, spleen size was no significant correlation. AXL expression in CML patients with newly diagnosed white blood cell count was significantly higher relevant. |
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