Publication: Relevancia del microambiente medular en el desarrollo de la leucemia linfoblástica aguda infantil: papel del BMP4
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2017-09-12
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Universidad Complutense de Madrid
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Abstract
La leucemia linfoblástica aguda es una enfermedad hematológica muy frecuente en edad infantil, que se origina por diversas alteraciones genéticas que alteran la capacidad de proliferación y diferenciación de los progenitores linfoides, contribuyendo a su acumulación en médula ósea. La clasificación de los pacientes en el momento del diagnóstico en diferentes grupos de riesgo de recaída ha permitido aumentar la tasa de supervivencia hasta un 90%; sin embargo, un 10-15% de ellos sigue recayendo en la enfermedad, lo que hace necesario el desarrollo de nuevas técnicas de diagnóstico y tratamiento 1. En este sentido, en los últimos años, además del estudio de las características de las células leucémicas, numerosos trabajos han centrado su interés en conocer las características del microambiente donde estas se asientan. En concreto, los estudios en la población de células madre mesenquimales (MSCs) en pacientes con enfermedades hematológicas han revelado alteraciones en su capacidad de proliferación, diferenciación y producción de citoquinas 2-6. Sin embargo, su función inmunosupresora, principal característica de estas células, apenas ha sido estudiada y en los escasos trabajos en que se ha analizado, los cambios observados han sido atribuidos a alteraciones dirigidas por las células tumorales para favorecer la progresión de la enfermedad 5-7. Asimismo, nuevos estudios muestran un comportamiento diferencial de las MSCs de los pacientes dependiente del riesgo de recaída que podría ser determinante en el pronóstico de la enfermedad 8. Las células NK son una población linfoide con capacidad para reconocer células tumorales o infectadas de manera directa y eliminarlas gracias a su maquinaria lítica. Producen además citoquinas y quimioquinas, promoviendo la activación de células de la inmunidad adaptativa 9. Estas propiedades han hecho que sean consideradas los principales agentes antitumorales del organismo. Sin embargo, en muchos tumores se ha descrito una capacidad funcional comprometida de las mismas haciéndolas incapaces de hacer frente a la transformación maligna...
Acute lymphoblastic leukaemia is the most common childhood malignancy, caused by multiple factors. These factors, that include exogenous and endogenous exposures and genetic susceptibility, disrupt proliferation and differentiation ability of lymphoid precursors, which accumulate in bone marrow. Although risk-directed trials of chemotherapy have resulted in long-term event free survival rates of 90%, approximately 10-15% of children relapse 1. In recent years, several reports have emphasized the importance of bone marrow microenvironment in the development of the disease. In particular, they have studied the characteristics of mesenchymal stem cells (MSCs), key components of the microenvironment involved in the maintenance of leukemic cells. These studies reported differences in proliferation and differentiation ability, cytokine production and, to a lesser extent, immunomodulatory activity, between MSCs isolated from patients with different hematopoietic disorders and healthy donors 2-6. However, in most cases, these alterations have been suggested to be directed by tumor cells for their own benefit 5- 7. Likewise, in a study with myelodysplastic syndrome patients, authors have found that MSCs from high-risk and low-risk patients exhibit differences in immunomodulatory capacities on DC maturation, which would be decisive in disease prognosis 8. NK cells are a subset of lymphoid cells, which constitutively express lytic machinery able to kill infected or tumor cells, and produce cytokines and chemokines that promote adaptive immune response 9. These cells are the major effector antitumor agents; however, their activity may be eluded by the tumor microenvironment...
Acute lymphoblastic leukaemia is the most common childhood malignancy, caused by multiple factors. These factors, that include exogenous and endogenous exposures and genetic susceptibility, disrupt proliferation and differentiation ability of lymphoid precursors, which accumulate in bone marrow. Although risk-directed trials of chemotherapy have resulted in long-term event free survival rates of 90%, approximately 10-15% of children relapse 1. In recent years, several reports have emphasized the importance of bone marrow microenvironment in the development of the disease. In particular, they have studied the characteristics of mesenchymal stem cells (MSCs), key components of the microenvironment involved in the maintenance of leukemic cells. These studies reported differences in proliferation and differentiation ability, cytokine production and, to a lesser extent, immunomodulatory activity, between MSCs isolated from patients with different hematopoietic disorders and healthy donors 2-6. However, in most cases, these alterations have been suggested to be directed by tumor cells for their own benefit 5- 7. Likewise, in a study with myelodysplastic syndrome patients, authors have found that MSCs from high-risk and low-risk patients exhibit differences in immunomodulatory capacities on DC maturation, which would be decisive in disease prognosis 8. NK cells are a subset of lymphoid cells, which constitutively express lytic machinery able to kill infected or tumor cells, and produce cytokines and chemokines that promote adaptive immune response 9. These cells are the major effector antitumor agents; however, their activity may be eluded by the tumor microenvironment...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Biología Celular, leída el 14-06-2016