Estudio de las alteraciones epigenéticas y búsqueda de nuevos tratamientos en la leucemia aguda linfoblástica

Resumen

Study of epigenetic alterations and search for new treatments for acute lymphoblastic leukaemia Acute lymphoblastic leukemia (ALL), the most common kind of cancer in children, is associated with a number of genetic lesions responsible for impairment of normal cellular behavior. Chromosomal translocations identify unique subtypes of the disease and although detected in less than 50% of patients with B-ALL and in a significantly lower percentage of T-ALL, they have been associated with specific prognostic groups. Recent evidence suggests that translocations act in concert with other genetic lesions to induce overt leukemia including deletion of genes. Further, the role of aberrant epigenetic modifications in hematological malignances has clearly recognized in the last years. In this work, we demonstrated the involvement of epigenetic inactivation of the tumor suppressor pathway TP53 and in the miRNAs regulation. We have shown that the use of new drugs in the treatment of ALL would allow the correction of these abnormalities, by epigenetic using 5-aza-2`deoxicitydine (demethylase) or LBH589 (histone deacetylase inhibitor) and using other strategies that activate genes required for proper cell control such as Curcumin, PD-03329991 or Nutlin-3. Moreover, we have developed two animal models of ALL who have allowed us to test the therapeutic effect of LBH589 in vivo as well as to observe the synergistic effect of its combination with other compounds used as chemoterapy of the patients with ALL, showing that LBH589 represents a novel candidate for treatment of patients with ALL.