MYC as therapeutic target in leukemia and lymphoma

MYC is a transcription factor that is involved in the expression of many genes. Deregulated MYC is found in about half of human tumors, being more prevalent in hematological neoplasms. Deregulation mechanisms include chromosomal translocation (particularly in lymphoma), amplification, and hyperactivation of MYC transcription. Here we review MYC involvement in the major types of leukemia and lymphoma. MYC rearrangements appear in all Burkitt lymphomas and are common in other lymphoma types, whereas in acute lymphoblastic leukemia, acute myeloid leukemia, lymphoproliferative, and myeloproferative diseases, they are less frequent. However, MYC overexpression is present in all types of hematological malignancies and often correlates with a worse prognosis. Data in leukemia-derived cells and in animal models of lymphomagenesis and leukemogenesis suggest that MYC would be a good therapeutic target. Several MYC-directed therapies have been assayed in preclinical settings and even in clinical trials. First, peptides and small molecules that interrupt the MYC–MAX interaction impair MYC-mediated tumorogenesis in several mouse models of solid tumors, although not yet in lymphoma and leukemia models. Second, there are a number of small molecules inhibiting the interaction of MYC–MAX heterodimers with DNA, still in the preclinical research phase. Third, inhibitors of MYC expression via the inhibition of BRD4 (a reader of acetylated histones) have been shown to control the growth of MYC-transformed leukemia and lymphoma cells and are being used in clinic trials. Finally, we review a number of promising MYC-mediated synthetic lethal approaches that are under study and have been tested in hematopoietic neoplasms

Regulación epigenética de BCL6 en linforma agresivo de células B: papel regulador de la cromatina CTCF y efectos de un inhibidor de histona deacetilasa

ABSTRACT: BCL6 is a transcriptional repressor expressed in B-lymphocytes and which expression pattern is highly regulated. Several mechanisms have been described, but BCL6 is deregulated in some types of lymphomas including Burkitt lymphoma, follicular lymphoma and diffuse large B cell lymphoma. CTCF is a chromatin regulator. Among the multiple functions of CTCF, its role in the epigenetic regulation of genes involved in cancer such us p53, RB, MYC, etc is highlighted. Alterations in epigenetic mechanisms are frequently found in hematological diseases. Epigenetic alterations are potentially reversible using drugs. Among them is romidepsin, a histone deacetylase inhibitor already successfully used for the treatment of some types of T-cell lymphoma. This Thesis work provides new insights in the mechanisms involved in the epigenetic regulation of BCL6 and the role of CTCF and romidepsin.RESUMEN: BCL6 es un represor transcripcional cuyo patrón de expresión está altamente regulado y se han descrito varios mecanismos, pero se ve alterado en algunos linfomas incluyendo el linfoma de Burkitt, linfoma folicular y linfoma difuso de célula B grande. CTCF es un regulador de la cromatina multivalente. Entre las múltiples funciones atribuidas a CTCF destaca su implicación en diferentes aspectos de la regulación epigenética de numerosos genes involucrados en cáncer como p53, RB, MYC, etc. Mecanismos epigenéticos (como metilación del DNA y las modificaciones posttraduccionales de las histonas) se encuentran frecuentemente alterados en enfermedades hematológicas. Las alteraciones epigenéticas son potencialmente reversibles mediante el uso de fármacos. Entre ellos se encuentra la romidepsina, un inhibidor de la deacetilación de las histonas, que ya está siendo usado con éxito para el tratamiento de algunos tipos de linfomas de células T. En esta Tesis se aportan nuevos mecanismos y conocimiento en relación a la regulación epigenética de BCL6 en linfomas B y el papel que en ella ejercen CTCF