MIR4435-2HG as a possible novel predictive biomarker of chemotherapy response and death in pediatric B-cell ALL.

Introduction: Although B-cell acute lymphoblastic leukemia (B-cell ALL) survival rates have improved in recent years, Hispanic children continue to have poorer survival rates. There are few tools available to identify at the time of diagnosis whether the patient will respond to induction therapy. Our goal was to identify predictive biomarkers of treatment response, which could also serve as prognostic biomarkers of death, by identifying methylated and differentially expressed genes between patients with positive minimal residual disease (MRD+) and negative minimal residual disease (MRD-). Methods: DNA and RNA were extracted from tumor blasts separated by immunomagnetic columns. Illumina MethlationEPIC and mRNA sequencing assays were performed on 13 bone marrows from Hispanic children with B-cell ALL. Partek Flow was used for transcript mapping and quantification, followed by differential expression analysis using DEseq2. DNA methylation analyses were performed with Partek Genomic Suite and Genome Studio. Gene expression and differential methylation were compared between patients with MRD-/- and MRD+/+ at the end of induction chemotherapy. Overexpressed and hypomethylated genes were selected and validated by RT-qPCR in samples of an independent validation cohort. The predictive ability of the genes was assessed by logistic regression. Survival and Cox regression analyses were performed to determine the association of genes with death. Results: DAPK1, BOC, CNKSR3, MIR4435-2HG, CTHRC1, NPDC1, SLC45A3, ITGA6, and ASCL2 were overexpressed and hypomethylated in MRD+/+ patients. Overexpression was also validated by RT-qPCR. DAPK1, BOC, ASCL2, and CNKSR3 can predict refractoriness, but MIR4435-2HG is the best predictor. Additionally, higher expression of MIR4435-2HG increases the probability of non-response, death, and the risk of death. Finally, MIR4435-2HG overexpression, together with MRD+, are associated with poorer survival, and together with overexpression of DAPK1 and ASCL2, it could improve the risk classification of patients with normal karyotype. Conclusion: MIR4435-2HG is a potential predictive biomarker of treatment response and death in children with B-cell ALL.

Guía de atención integral para la detección oportuna, diagnóstico, tratamiento y seguimiento de leucemia linfoide aguda en niños, niñas y adolescentes / Comprehensive guide for early detection, diagnosis, treatment and monitoring of acute leukemia lymphocytic leukaemiaid children and teens

La leucemia linfoide aguda (LLA) es el cáncer más frecuente en niños. A nivel mundial se estima que cerca del 30% corresponde a la totalidad de las neoplasias malignas que se presentan en niños y, de estas, más del 75% son LLA. En Colombia no existe aún un registro nacional de cáncer que nos permita evaluar exactamente la carga de la enfermedad por esta patología; sin embargo, se estima que se presentan aproximadamente 2.080 casos nuevos por año de cáncer en pacientes pediátricos y de estos 500 corresponden a LLA. Con el objetivo de disminuir la mortalidad y mejorar la oportunidad en el diagnóstico y en el tratamiento de los niños afectados por esta patología, se desarrolló esta Guía de práctica clínica (GPC) como producto del trabajo durante meses de un grupo organizado y motivado de médicos especialistas en el área (epidemiólogos, economistas, entre otros), quienes elaboraron recomendaciones para las diferentes etapas tanto para la prevención, sospecha, diagnóstico, tratamiento, seguimiento de los niños y adolescentes con diagnóstico de LLA.

Acute lymphocytic leukaemia (ALL) is the most common cancer in children. Globally, it is estimated that nearly 30% correspond to the total of malignant tumours in children, and 75% of them are ALL. There is no national cancer registry in Colombia that would allow us to precisely assess the burden of the disease for this condition; however, calculations have shown that there are 2,080 new paediatric cancer cases every year, and of those 500 correspond to ALL. With the goal of reducing mortality and improving the chances for a diagnosis and treatment of children affected by this condition, the present clinical practice guide (CPG) was developed after a work of months carried out by an organised and motivated group of physicians specialised in the field (epidemiologists and economists, among others), who formulated recommendations for the different stages: prevention, suspicion, diagnosis, treatment and follow-up of children and teens diagnosed with ALL.

Mesenchymal stem cells promote leukaemic cells aberrant phenotype from B-cell acute lymphoblastic leukaemia.

BACKGROUND AND OBJECTIVES: The role of bone marrow-mesenchymal stem cells (BM-MSC) in leukaemic cell control is controversial. The purpose of this work was to evaluate BM-MSC role regarding the viability, proliferation and immunophenotype of normal B-cell precursors from control (Ct) patients and leukaemic cells from B-acute lymphoblastic leukaemia (B-ALL) patients. PATIENTS AND METHODS: BM-MSC were isolated and characterised from voluntary donors. Mononuclear cells isolated from Ct and B-ALL bone marrow samples were cultured in the presence or absence of BM-MSC for 7days. Cell viability was determined with LIVE/DEAD and proliferation index evaluated by CFSE labelling. Cell population immunophenotypes were characterised by estimating CD19, CD10, CD20 and CD45 antigens by flow cytometry. RESULTS: After co-culture, B-ALL cells exhibited higher viability (20-40%) as compared to just cells (3-10%). Ct and B-ALL absolute cell counts were higher in the presence of BM-MSC (Ct: 25/mm(3)cf8/mm(3), B-ALL: 15/mm(3)cf3/mm(3)). Normal B-cell subpopulations in co-culture had increased expression of CD19 and CD10 (Pre-pre B) and CD45 and CD20 antigens (Pre-B). B-ALL cells co-cultured with BM-MSC showed an increase in CD19 and CD20, although the greatest increase was observed in the CD10 antigen. CONCLUSIONS: Lymphoid cell maintenance, at early stages of differentiation, was significantly promoted by BM-MSC in normal and leukaemic cells. Co-cultures also modulated the expression of antigens associated with the B-ALL asynchronous phenotype as CD10 co-expressed with CD19 and CD20. To our knowledge, this is the first time that CD10, CD19 and CD20 leukaemic antigens have been reported as being regulated by BM-MSC.

Linfoma de célula grande en niños y adolescentes Instituto Nacional de Cancerología, Bogotá, (Colombia), 1980-2001 / Large cell lymphoma in children and adolescents of the Instituto Nacional de Cancerología E. S. E.: (Bogotá, Colombia): 1980-2001

Objetivo: Caracterizar y establecer la supervivencia de los pacientes pediátricos con linfoma de célula grande (LCG) que asistieron al Instituto Nacional de Cancerología, E.S.E., duarnte el periodo de 1980 a 2001.Materiales y métodos: Se revisaron las historias clínicas de 19 pacientes, se confirmó el diagnóstico ppor morfología y se estableció el inmunofenotipo con los anticuerpos CD20, CD30, CD43, CD45RB, CD45RO, CD68, CD3, ALK, tdt y S-100, se utilizaron la prueba exacta de Fisher para las asociaciones, el método de Kaplan- Meier para la supervivencia y la prueba de log-rank para comparar curvas de supervivencia. Resultados: Diez pacientes eran de sexo femenino;la mediana de edad fue de once años, con un rango de tres a dieciséis años; la localización más frecuente fue el cuello (siete casos); nueve pacientes estaban en el estadio I; el inmunofenotipo de mayor presentación fue el de células T, en 11 casos; trece pacientes entraron en remisión completa. A los dos años, la supervivencia libre de eventos fue de 47,3 por ciento; la supervivencia libre de enfermedad, de 99,8 por ciento, y la supervivencia global, de 68 por ciento; a los cinco años, la supervivenciaa libre de eventos fue de 28,8 por ciento. Conclusión: Se debe estudiar un número mayor de pacientes para obtener estimaciones más precisas en relación con las característcas clínicas y la supervivencia de niños y adolescentes con linfoma de célula grande.