RESUMEN
Overexpression of Aurora kinases is largely observed in many cancers, including hematologic malignancies. In this study, we investigated the effects and molecular mechanisms of Aurora kinase inhibitors in acute lymphoblastic leukemia (ALL). Western blot analysis showed that both Aurora-A and Aurora-B are overexpressed in ALL cell lines and primary ALL cells. Both VE-465 and VX-680 effectively inhibited Aurora kinase activities in nine ALL cell lines, which exhibited different susceptibilities to the inhibitors. Cells sensitive to Aurora kinase inhibitors underwent apoptosis at an IC50 of â¼10-30 nM and displayed a phenotype of Aurora-A inhibition, whereas cells resistant to Aurora kinase inhibitors (with an IC50 more than 10 µM) accumulated polyploidy, which may have resulted from Aurora-B inhibition. Drug susceptibility of ALL cell lines was not correlated with the expression level or activation status of Aurora kinases. Interestingly, RS4;11 and MV4;11 cells, which contain the MLL-AF4 gene, were both sensitive to Aurora kinase-A inhibitors treatment. Complementary DNA (cDNA) microarray analysis suggested that CDKN1A might govern the drug responsiveness of ALL cell lines in a TP53-independent manner. Most importantly, primary ALL cells with MLL-AF4 and CDKN1A expression were sensitive to Aurora kinase inhibitors. Our study suggests CDKN1A could be a potential biomarker in determining the drug responsiveness of Aurora kinase inhibitors in ALL, particularly in MLL-AF4-positive patients.
Asunto(s)
Aurora Quinasa A/antagonistas & inhibidores , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Proteínas de Fusión Oncogénica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Apoptosis/efectos de los fármacos , Western Blotting , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Humanos , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
SUMMARY: This study aimed to evaluate the frequency of the diverse causes of iron deficiency (ID) and iron deficiency anemia (IDA) and to investigate the treatment outcomes in children. ID was defined as a serum ferritin level<12 microg/L and a transferrin saturation<10%. IDA was established as ID combined with a low hemoglobin level judged by age and gender-specific reference intervals. A total of 116 ID patients were categorized into 4 groups: group I:<2 years old (n=45), group II: 2 to 10 years old (n=13), group III:>10 years old, male (n=18), and group IV: >10 years old, female (n=40). One hundred of them (86.2%) were diagnosed with IDA. The most common causes of ID were inadequate intake in group I (55.6%) and blood loss in groups II (46.1%) and IV (37.5%). Helicobacter pylori-associated ID mainly occurred in children more than 10 years old. Forty-five of 57 (78.9%) IDA patients who had underlying diseases treatment and/or iron supplementation for 3 months recovered their hemoglobin levels (follow-up range: 6-27 mo). In conclusion, the peak incidences of childhood ID were ages under 2 years old and 10-18 years old. Different age groups and sexes showed characteristic etiologies. The outcomes of childhood ID were good.