ABSTRACT
ABCB1/P-glycoprotein (Pgp) and ABCG2/BCRP overexpression have been described as related to imatinib resistance in chronic myeloid leukemia (CML). We showed in CML cells from 55 patients that Pgp activity was more frequently detected than BCRP activity (p=0.0074). Imatinib-induced Crkl phosphorylated protein (pCrkl) reduction was more pronounced in K562 (Pgp-negative) than in K562-Lucena (Pgp-positive) CML cell line. Expressive pCrkl reduction levels after in vitro imatinib treatment was observed in samples from patients exhibiting lower Pgp activity levels compared with patients exhibiting higher Pgp activity levels (p=0.0045). Pgp activity in association with pCrkl reduction levels might help to distinguish between imatinib-resistant and imatinib-sensitive CML cells.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Proto-Oncogene Proteins c-crk/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/therapeutic use , Benzamides/therapeutic use , Biomarkers, Tumor/metabolism , Child , Child, Preschool , Drug Resistance, Neoplasm , Female , Humans , Imatinib Mesylate , K562 Cells , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , MCF-7 Cells , Male , Middle Aged , Phosphorylation , Piperazines/therapeutic use , Protein Kinases/metabolism , Pyrimidines/therapeutic use , Young AdultABSTRACT
P-glycoprotein (Pgp) and XIAP co-expression has been discussed in the process of the acquisition of multidrug resistance (MDR) in cancer. Here, we evaluated XIAP and Pgp expression in chronic myeloid leukemia (CML) samples, showing a positive correlation between them. Furthermore, we evaluated the effects of imatinib in XIAP and Pgp expression using CML cell lines K562 (Pgp(-)) and K562-Lucena (Pgp(+)). Imatinib increased XIAP and Pgp expression in K562-Lucena cells, while in K562 cells a downregulation of these proteins was observed, suggesting that imatinib induces an increment of MDR phenotype of CML cells that previously exhibit high levels of Pgp/XIAP co-expression.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Antineoplastic Agents/pharmacology , Benzamides/pharmacology , Drug Resistance, Neoplasm/genetics , Gene Expression , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Piperazines/pharmacology , Pyrimidines/pharmacology , X-Linked Inhibitor of Apoptosis Protein/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Apoptosis/drug effects , Apoptosis/genetics , Cell Line, Tumor , Cell Survival/drug effects , Child , Female , Gene Expression Regulation, Leukemic/drug effects , Gene Knockdown Techniques , Humans , Imatinib Mesylate , Inhibitor of Apoptosis Proteins/genetics , Inhibitor of Apoptosis Proteins/metabolism , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Male , Middle Aged , Protein Kinase Inhibitors/pharmacology , RNA Interference , Survivin , X-Linked Inhibitor of Apoptosis Protein/metabolism , Young AdultABSTRACT
A 54-year-old woman was diagnosed with infiltrative ductal breast carcinoma. Two years after treatment, the patient developed an acute myeloid leukemia (AML) which harbored del(11q23) in 8% of the blast cells. The patient was submitted for allogeneic stem cell transplantation (aSCT) from her HLA-compatible sister. Ten months after transplantation, she relapsed with an AML with basophilic maturation characterized by CD45(low) CD33(high), CD117âº, CD13(-/+), HLA Dr(high), CD123(high), and CD203c⺠blast cells lacking expression of CD7, CD10, CD34, CD15, CD14, CD56, CD36, CD64, and cytoplasmic tryptase. Karyotype analysis showed the emergence of a new clone with t(2;14) and FISH analysis indicated the presence of MLL gene rearrangement consistent with del(11q23). Interestingly, AML blast cell DNA tested with microsatellite markers showed the same pattern as the donor's, suggesting that this AML emerged from donor cells. Additionally, polymorphisms of the XPA, XPD, XRCC1, XRCC3 and RAD51 DNA repair genes revealed three unfavorable alleles with low DNA repair capacity.In summary, we report the first case of AML involving XPD and XRCC3 polymorphisms from donor origin following allogeneic stem cell transplantation and highlight the potential need for careful analysis of DNA repair gene polymorphisms in selecting candidate donors prior to allogeneic stem cell transplantation.
Subject(s)
Breast Neoplasms/therapy , DNA-Binding Proteins/metabolism , Leukemia, Myeloid/etiology , Stem Cell Transplantation/adverse effects , Xeroderma Pigmentosum Group D Protein/metabolism , Antineoplastic Agents/therapeutic use , Cytogenetic Analysis , DNA-Binding Proteins/genetics , Fatal Outcome , Female , Gene Expression Regulation , Genetic Predisposition to Disease , Humans , Leukemia, Myeloid/pathology , Microsatellite Repeats , Middle Aged , Polymorphism, Genetic , Transplantation, Homologous , Xeroderma Pigmentosum Group D Protein/geneticsABSTRACT
The involvement of the multidrug resistance (MDR) mediated by ABC transporter proteins P-glycoprotein (Pgp) and multidrug resistance-associated protein-1 (MRP1) overexpressions in patients with chronic myeloid leukemia (CML) are not completely understood. Pgp and MRP1 expressions and activity were analyzed in samples from 158 patients with chronic myeloid leukemia (CML). Using flow cytometry, Pgp expression was more frequently observed in early chronic (P = 0.00) and in advanced (P = 0.02) CML phases when it was compared to MRP1 expression. Variation of MDR expression and activity were observed during the CML evolution in patients previously treated with interferon and imatinib. In the K562-Lucena cell line, Pgp positive, imatinib caused an enhancing in Pgp expression at protein and mRNA levels, whereas in the Pgp negative cell line, this drug was capable of decreasing MDR1/Pgp mRNA levels. Our result emphasizes the importance of understanding the different aspects of MDR status in patients with CML when they are under investigation in determining imatinib resistance.
