RESUMEN
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.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Proteínas Proto-Oncogénicas c-crk/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Benzamidas/uso terapéutico , Biomarcadores de Tumor/metabolismo , Niño , Preescolar , Resistencia a Antineoplásicos , Femenino , Humanos , Mesilato de Imatinib , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Células MCF-7 , Masculino , Persona de Mediana Edad , Fosforilación , Piperazinas/uso terapéutico , Proteínas Quinasas/metabolismo , Pirimidinas/uso terapéutico , Adulto JovenRESUMEN
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.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Antineoplásicos/farmacología , Benzamidas/farmacología , Resistencia a Antineoplásicos/genética , Expresión Génica , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Piperazinas/farmacología , Pirimidinas/farmacología , Proteína Inhibidora de la Apoptosis Ligada a X/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis/efectos de los fármacos , Apoptosis/genética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Niño , Femenino , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Mesilato de Imatinib , Proteínas Inhibidoras de la Apoptosis/genética , Proteínas Inhibidoras de la Apoptosis/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/farmacología , Interferencia de ARN , Survivin , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismo , Adulto JovenRESUMEN
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.
Asunto(s)
Neoplasias de la Mama/terapia , Proteínas de Unión al ADN/metabolismo , Leucemia Mieloide/etiología , Trasplante de Células Madre/efectos adversos , Proteína de la Xerodermia Pigmentosa del Grupo D/metabolismo , Antineoplásicos/uso terapéutico , Análisis Citogenético , Proteínas de Unión al ADN/genética , Resultado Fatal , Femenino , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Humanos , Leucemia Mieloide/patología , Repeticiones de Microsatélite , Persona de Mediana Edad , Polimorfismo Genético , Trasplante Homólogo , Proteína de la Xerodermia Pigmentosa del Grupo D/genéticaRESUMEN
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.