Altered Arylamine N-acetyltransferase 1 and miR-1290 Levels in Childhood Acute Lymphoblastic Leukemia: A Pilot Study.

BACKGROUND/AIM: Arylamine N-acetyltransferase 1 and 2 (NAT1 and NAT2) are drug-metabolizing enzymes that play a key role in the development of acute lymphoblastic leukemia (ALL). MATERIALS AND METHODS: This study evaluated NAT1 and NAT2 mRNA and protein expression and their enzymatic activity in peripheral blood mononuclear cells (PBMC) from patients with ALL (n=20) and healthy children (n=19) and explored the mechanisms that regulate these enzymes in ALL such as microRNAs (miR-1290, miR-26b) and SNPs. RESULTS: PBMC from patients with ALL showed a decrease in NAT1 mRNA and protein expression. In addition, NAT1 enzymatic activity was decreased in patients with ALL. There was no influence of SNP 559 C>T or 560 G>A on low NAT1 activity. The lower expression of NAT1 might be related to the loss of acetylated histone H3K14 in the NAT1 gene promoter in patients with ALL and the higher relative expression of miR-1290 in the plasma of patients with relapsed ALL compared with healthy controls. There were significantly fewer CD3+/NAT1+ double-positive cells in patients who relapsed compared with control subjects. Based on a t-distributed stochastic neighbor embedding algorithm, CD19+ cells that reappeared in patients with relapse showed low NAT1 expression. In contrast, for NAT2, there were no significant results. CONCLUSION: The expression and function of NAT1 and miR-1290 levels could be involved in modulating immune cells altered in ALL.

Population pharmacokinetics of methotrexate in Mexican pediatric patients with acute lymphoblastic leukemia.

PURPOSE: To develop and validate a population pharmacokinetic model of Methotrexate (MTX) in Mexican children with acute lymphoblastic leukemia (ALL) for the design of personalized dosage regimens based on the anthropometric and physiological characteristics of each patient. METHODS: A prospective study was developed in 50 children (1-15 years old) with ALL diagnosis attended at Pediatric Hemato-Oncology Service from Hospital Central "Dr. Ignacio Morones Prieto" and under treatment with high doses of MTX administered in 24-h continuous intravenous infusion. Plasma concentrations of MTX were determined in blood samples collected at 24, 36, 42 or 48 h post-infusion, by means of the CMIA immunoassay. The development of the population pharmacokinetic model was performed using the NONMEM® software evaluating the covariates that influence in clearance (CL), intercompartmental clearance (Q), central (Vc) and peripheral (Vp) volume of distribution of MTX. RESULTS: A two-compartment open model was selected to describe concentration-time data and body surface area (BSA) was the covariate that influences on MTX total CL. The population pharmacokinetic model obtained was: CL (L/h) = 6.5 × BSA0.62, Vc (L) = 0.36 × Weight, Q (L/h) = 0.41 and Vp (L) = 3.2. Internal validation was performed by bootstrap and visual predictive check. Predictive performance of final model was evaluated by external validation in a different group of patients. Initial MTX dosing regimens were established by stochastic simulation with final population pharmacokinetic model. CONCLUSIONS: The establishment of MTX dosing criteria in children with ALL should be adjusted based on the BSA of each patient to optimize oncological therapy and reduce the development of adverse effects. Therapeutic drug monitoring is an essential tool to individualize MTX doses to reduce toxicity and improve patients' outcomes.

Genetic polymorphisms of arylamine N-acetyltransferases 1 and 2 and the likelihood of developing pediatric acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is one of the main causes of death in children and is associated with both genetic susceptibility and environmental factors. Genes encoding the arylamine N-acetyltransferases 1 and 2 (NAT1 and NAT2) isoenzymes are highly polymorphic among populations. Single-nucleotide polymorphism analysis was performed by real-time polymerase chain reaction from the genomic DNA of 225 healthy subjects and 57 children with ALL diagnoses. Significant associations were found between the development of ALL and the presence of the haplotypes NAT1*3 (Odds ratio [OR], 2.1), NAT1*4 (OR, 1.92), NAT2*6B (OR, 3.30), NAT2*6J (OR, 3.25) and NAT2*7A (OR, 2.45) and the NAT1 rapid (OR, 6.69) and NAT2 slow phenotypes (OR, 2.95). Our results indicate that haplotypes that provide rapid NAT1 and slow NAT2 acetylating phenotypes may influence the development of ALL in children.

[Prognostic value of pre-B immunophenotype in early treatment response among acute pediatric lymphoblast leukemia patients]. / Valor pronóstico del inmunofenotipo en la respuesta temprana de la leucemia aguda linfoblástica pre-B en niños.

OBJECTIVE: To determine the prognostic value of preB immunophenotype and its variants on early treatment response among of acute pediatric lymphoblast leukemia. PATIENTS AND METHODS: A case-control study nested in a cohort was carried out with male and female patients 15 years and younger with recently diagnosed pre-B lymphoblast leukemia. A panel of B, T, monoclonal antibodies of the myelo-monocytic and megakaryocytic cell type was used. Response was assessed by bone marrow aspiration 14 days post treatment. RESULTS: 54 patients were included. The median age was 7 years (2 months - 14 years) median leukocyte count was 13,450/mm3 (1200-986,000/mm3). We identified 29 cases with late pre-B immune phenotype, 19 cases with common pre B and 6 cases with early preB immunophenotype. Eleven, patients also displayed myeloid antigens. A significant association (p=0.034) was found between early treatment response and the presence of myeloid antigens. No association was found between the pre-B immunophenotype, age and leukocyte count with early treatment response (p=0.264). CONCLUSIONS: We need to pay special emphasis on early treatment response in children with lymphoblast leukemia as our study did not corroborate the common finding that clinical factors and immune phenotype can be predictive factors.

Valor pronóstico del inmunofenotipo en la respuesta temprana de la leucemia aguda linfoblástica pre-B en niños / Prognostic value of pre-B immunophenotype in early treatment response among acute pediatric lymphoblast leukemia patients

Objetivo: Determinar el valor pronóstico del inmunofenotipo pre B con sus variantes en la respuesta temprana al tratamiento de la leucemia aguda linfoblástica pediátrica, ajustando edad y cifra de leucocitos inicial. Pacientes y método: Se realizó un estudio de casos y controles anidado en una cohorte con pacientes menores de 15 años de edad, de los dos géneros, con leucemia aguda linfoblástica pre B de diagnóstico reciente. Se utilizó un panel de anticuerpos monoclonales específicos de la estirpe B, T, monocito mielocito y megacariocítica. Se evaluó la respuesta después de 14 días de tratamiento mediante aspirado de médula ósea. Resultados: Se incluyeron 54 pacientes. La mediana de edad fue de 7 años (2 m 14 años), la mediana de cifra de leucocitos fue 13,450/mm³ (1200-986,000/mm³). Se identificaron 29 casos con inmunofenotipo Pre B tardío, 19 casos pre B común y 6 casos de pre B precoz. Once pacientes presentaron antígenos mieloides asociados. Se encontró asociación significativa (p=0.034) entre respuesta temprana y la presencia de antígenos mieloides. No se demostró asociación entre las variantes del inmunofenotipo pre B, edad y cifra de leucocitos con la respuesta temprana (p=0.264). Conclusiones: Es necesario estudiar directamente la respuesta tem prana al tratamiento en los niños con leucemia linfoblástica ya que en nuestra muestra de pacientes los factores clínicos y el inmunofenotipo no fueron predictivos de ésta.

Objective: To determine the prognostic value of pre B immunophenotype and its variants on early treatment response among of acute pediatric lymphoblast leukemia. Patients and methods: A case control study nested in a cohort was carried out with male and female patients 15 years and younger with recently diagnosed pre B lymphoblast leukemia. A panel of B, T, monoclonal antibodies of the myelo monocytic and megakaryocytic cell type was used. Response was assessed by bone marrow aspiration 14 days post treatment. Results: 54 patients were included. The median age was 7 years (2 months - 14 years) median leukocyte count was 13,450/mm3 (1200-986,000/mm3). We identified 29 cases with late pre B immune phenotype, 19 cases with common pre B and 6 cases with early pre B immunophenotype. Eleven patients also displayed myeloid antigens. A significant association (p=0.034) was found between early treatment response and the presence of myeloid antigens. No association was found between the pre B immunophenotype, age and leukocyte count with early treatment response (p=0.264). Conclusions: We need to pay special emphasis on early treatment response in children with lymphoblast leukemia as our study did not corroborate the common finding that clinical factors and immune phenotype can be predictive factors.