title: MYC deregulation in lymphoid tumors: molecular mechanisms, clinical consequences and therapeutic implications.
abstract: MYC is one of the most frequently deregulated oncogenes in human malignancies. It encodes a leucine zipper transcription factor that modulates a broad spectrum of cellular genes responsible for enhancing cell proliferation, cellular metabolism, growth, angiogenesis, metastasis, genomic instability, stem cell self-renewal and reduced differentiation. MYC functions predominantly as an amplifier of expression of already active genes, potentiating the pre-existing transcriptional program, although it can also repress certain transcriptional targets. In mouse models, MYC induces lymphomas, but requires cooperation with other lesions, including inactivation of the p53 pathway, structural alterations of BCL2 family members, or increased PI3K activity. In human B-cell tumors, MYC rearrangements involving the 8q24 region and immunoglobulin heavy or light genes are a hallmark of Burkitt lymphoma (BL), but can also occur in other lymphoid malignancies, that include diffuse large B-cell lymphoma (DLBCL), B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma (BCLU), plasma cell myeloma (PCM), mantle cell lymphoma (MCL) and plasmablastic lymphoma. For non-BL lymphoid malignancies, MYC fusions represent secondary genetic events and exist in the context of complex karyotypes. Regardless of the mechanism deregulating MYC, lymphomas over-expressing MYC are addicted to this oncogene, highlighting the potential clinical utility of MYC targeting strategies. Several promising approaches for pharmaceutical intervention have been suggested which are now in preclinical or clinical development. Herein, we therefore review the molecular pathogenetic mechanisms associated with MYC deregulation in human B-cell lymphomas and their implications for therapies targeting MYC.
authors.affiliation: Institute of Hematology and Transfusion Medicine, Department of Diagnostic Hematology, Indiry Gandhi Str. 14, 02-776 Warsaw, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Sewastianik
authors.affiliation: Institute of Hematology and Transfusion Medicine, Department of Diagnostic Hematology, Indiry Gandhi Str. 14, 02-776 Warsaw, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Prochorec-Sobieszek
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Department of Medical Oncology, 450 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Chapuy
authors.affiliation: Institute of Hematology and Transfusion Medicine, Department of Diagnostic Hematology, Indiry Gandhi Str. 14, 02-776 Warsaw, Poland. Electronic address: pjuszczynski@ihit.waw.pl.
authors.forename: Przemysław
authors.initials: P
authors.lastname: Juszczyński
mesh_terms: D000818:Animals; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006801:Humans; D016393:Lymphoma, B-Cell / Q000209:etiology / Q000235:genetics* / Q000628:therapy; D051379:Mice; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*
chemical_list: D016271:Proto-Oncogene Proteins c-myc
keywords: Burkitt lymphoma; Diffuse large B-cell lymphoma; Double hit lymphoma; MYC; Targeted therapy