The effect of drug transporter gene polymorphisms on susceptibility to imatinib in chronic myelogenous leukemia / 中国肿瘤临床

As a first generation tyrosine kinase inhibitor, imatinib is the gold standard drug for the clinical treatment of chronic myelog-enous leukemia. However, interindividual differences in resistance and response to imatinib have been widely observed. In vivo and in vitro studies have confirmed that ATP-binding cassette transporters, organic cation transporters, and organic anion transporting poly-peptides have a large effect on imatinib pharmacokinetics and pharmacodynamics. In addition, the gene polymorphisms of drug trans-porters can directly or indirectly influence the intracellular concentration of imatinib, resulting in differences in treatment efficacy among chronic myelogenous leukemia patients. This review profiles the effect of drug transporter gene polymorphisms on susceptibili-ty to imatinib in chronic myelogenous leukemia so as to provide reference to further clinical researches.

Influence of Gleevec on expression of miR-146a,miR-29b and DNMT in K562 cells / 重庆医学

Objective To investigate the changes of microRNA (miR)-146a ,miR-29b expression levels and the 3 kinds of meth-ylase DNMT1 ,DNMT3a and DNMT3b levels in K562 cell lines after BCR/ABL inhibitor Gleevec treatment .Methods The half maximal inhibitory concentration(IC50 ) of Gleevec on K562 cells was detected by the MTT method .The stem loop primers method and the fluorogenic quantitative PCR were adopted to detect miRNAs and the methylase gene level .Results IC50 of Gleevec acting on K562 cells was 40 .85μmol/L .After Gleevec action ,miR-29b showed the increasing trend ,but 3 kinds of methylase expression level were decreased to some extent .Gleevec could significantly increase the miR-146a level in K562 cells(P<0 .05) .Conclusion Gleevec can influence the expression of miR-146a ,miR-29b and DNMTs levels in K562 cells .

T-lineage blast crisis of chronic myelogenous leukemia: simple record of 4 cases.

Blast crisis (BC) transformation in chronic myelogenous leukemia (CML) can involve each differentiation lineage of the hematopoietic system, i.e. granulocyte, monocyte, erythrocyte, megakaryocyte, and lymphocyte lineage. The lymphoid blast crisis (BC) leukemia cells usually belong to B-lineage, commonly having the phenotype of Pre-B stage of the B-lineage, in which cell-surface immunoglobulin (sIg) is not yet expressed. In contrast, T-lineage BC of CML is extremely rare. The objective of this study is to describe the fenotype, fusion transcript of bcr-abl, TdT, and cytoplasmic CD3 in T-lineage BC CML cases. Case report study. This report shows a simple summary of 4 cases of T-lineage BC of CML which have been collected in the phenotypic and genotypic analysis study for 17 years (1987-2004). In all cases, the chromosomal analysis revealed the presence of t(9;22)(q34;q11) at presentation. Cell surface analysis were done at diagnosis. Cases’ mononuclear cells stored as 10% DMSO were retrieved to be performed reverse transcription (RT) PCR BCR-ABL multiplex to demonstrate the presence of the fusion transcript of bcr-abl. RT-PCR was also performed for detecting the expression of cytoplasmic CD3ε and terminal deoxynucleotydil transferase (TdT). The results of cell surface antigen (CSA) at presentation showed that 1 case was CD7+, CD5-, and CD2-; 1 case CD7+, CD5+, and CD2-; and 2 cases CD7+, CD5+ and CD2+ indicating that all these T-lineage BC of CML cells show the phenotype of pre-(pro-) thymic stage phenotype. In the present study, two cases showed b2a2, one e1a2, and one negative bcr-abl transcript. The RT-PCR revealed the presence of CD3ε mRNA in all cases, and TdT mRNA in only one case. These results can constitute a basis for the future analysis of T-lineage BC of CML from now on.

The incidence of ABL Deletion on Derivative 9 Chromosome in Chronic Myelogenous Leukemia by Interphase Fluorescence In Situ Hybridization and its Association with Progression to Blast Crisis / 대한임상병리학회지

BACKGROUND: Philadelphia(Ph) chromosome is found in about 95 percent of chronic myelogenous leukemia(CML) patients. Ph chromosome results from a reciprocal translocation between the long arms of chromosomes 9 and 22, and the fusion gene, BCR-ABL contribute to oncogenesis. Three to five years after first diagnosis, CML progresses to the blast crisis, and is accompanied by secondary cytogenetic changes in about 85% of cases. In this study, we investigated the incidence of ABL deletion of derivative 9 chromosome in CML and evaluated the association between this deletion and progression to the blast crisis by interphase fluorescence in situ hybridization(FISH). METHOD: The subjects included in this study were a consecutive series of 58 patients who were diagnosed as CML at Seoul National University Hospital between January 1997 and April 2000. On 90 archival bone marrow aspirate samples from these 58 CML patients, interphase FISH was performed with a commercially available probe. RESULTS: The ABL deletion of derivative 9 chromosome was detected in 17(29.3%) of 58 patients with CML. Eighteen of 58 patients progressed to blast crisis in this period. ABL deletion was found in 7 of 18 patients with blast crisis, and not in 11 remainders. The mean duration from the diagnosis to blast crisis was 37.1 months in 7 patients with the ABL deletion, while the mean duration was 74.2 months in 11 patients without the ABL deletion. The mean duration from the diagnosis to blast crisis in patients with ABL deletion was significantly shorter than in patients without ABL deletion(P=0.043). CONCLUSIONS: We found that 29.3% of patients with CML had the ABL deletion on derivative 9 chromosome. In these patients, the time taken for evolution to blast crisis was significantly shorter than that of the patients without ABL deletion.

Analysis of Breakpoints of bcr-abl Fusion Gene Using RT-PCR / 대한임상병리학회지

BACKGROUND: Three types of chimeric mRNA can be expressed as a result of fusion of abl gene on chromosome 9 and bcr gene on chromosome 22. These are b3a2, b2a2, and e1a2. Rearranged mRNA of bcr-abl fusion gene is found in majority of chronic myelogenous leukemia (CML) and in 20% of acute lymphoblastic leukemia (ALL) and in other hematologic malignancies. METHODS: We have examined the chimeric mRNA by reverse transcriptase-polymerase chain reaction (RT-PCR) since 1994. Positive results for the chimeric mRNA were 167 (118 patients) out of 714 examined cases. 94 patients with CML irrespective of the disease course, 49 with ALL, 120 with acute myelogenous leukemia, 11 with acute mixed leukemia, and 7 with myelodysplastic syndrome were included. RESULTS: 97.9% (92/94) of patients with CML, 40% (20/49) of ALL, 45% (5/11) of acute mixed leukemia, and 14% (1/7) of myelodysplastic syndrome were positive for bcr-abl rearrangement. In CML, positive cases were with b3a2 (64%), b2a2 (32.6%), and b3a2/b2a2 (2.2%). One patient with CML-like feature expressed e1a2 type mRNA. In adult ALL, 62.5% (10/16) expressed minor-bcr (e1a2). CONCLUSIONS: The bcr-abl fusion gene was positive in various hematologic diseases as well as CML and that fact indicates the dysfunction of primitive pleuripotent stem cells. Various expressions and changes of mRNA types in bcr-abl fusion gene might be due to alternative splicing mechanism and detection sensitivity of RT-PCR when two types were intermingled. We should be aware of these facts when interpretating the results.