Targeting Epigenetic Circuits in B-Cell Lymphomas

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ABSTRACT The principal investigator is a physician scientist who has contributed significant discoveries to the cancer epigenetics field. He has published > 220 scientific papers, 130 of them in the past five years - many of them in high profile journals, and 30 of which were cited by the Faculty of 1000. He has been continuously NCI funded since completing his clinical training in 1997. His proposal will elucidate how B-cell lymphomas arise through disruption of an intricate network of epigenetic mechanisms that regulate and control the humoral immune response. In the generally accepted model for malignant transformation, somatic mutations cause normal cells to manifest aberrant phenotypic hallmarks that define them as malignant tumor cells. However, the PI proposes that malignant transformation occurs in a fundamentally different way in the germinal center (GC) B-cells that give rise to follicular lymphoma (FL) and diffuse large B-cell lymphomas (DLBCL). Specifically, he notes that upon their activation, GC B-cells surprisingly manifest many canonical cancer phenotypes (e.g. massive proliferation, tolerating genomic instability, etc.), which enables them to undergo rapid clonal evolution and immunoglobulin affinity maturation. Strikingly the GC reaction is a transient process after which B-cells extinguish this “pseudo-malignant” phenotype and undergo terminal differentiation, which highlights the PIs critical point that cancer phenotypes are not inherently irreversible. He proposes the novel hypothesis that FLs and DLBCLs arise from a failure of the GC B-cell phenotype to resolve due to disruption in the dynamic equilibrium between histone readers and writers. More specifically, he proposes that the immune synapse between T-follicular helper and GC B-cells normally signals to the epigenome to re-instate the B-cell differentiation program that is epigenetically silenced while B-cells undergo the GC reaction. He hypothesizes that the immune synapse fails to erase GC epigenetic marks and restore B-cell epigenetic marks in the presence of somatic mutations of the histone acetyltransferases CREBBP and EP300, and histone methyltransferases KMT2D and EZH2, which occur early during pathogenesis in ~80% of FL and DLBCL patients suggesting that lymphomas in essence represent uncontrolled GC reactions. Finally he predicts that FLs and DLBCLs with these mutations can be selectively treated using epigenetic-targeted drugs that counteract the effect of these mutations on the epigenome. This latter notion is supported for example by his finding that CREBBP mutant lymphomas are specifically biologically dependent on HDAC3, and that HDAC3 inhibitors reverse the epigenetic, transcriptional and biological effects of CREBBP mutation. For this research he has assembled unique and novel technologies such as GC organoids that allow precise, temporal observation of immune synapse signaling, the necessary genetically engineered mouse models, and extensive libraries of epigenomic profiles in primary human and murine lymphomas. The PI has a track record of translating his findings to the clinic and this proposal will lead to novel rationally designed clinical trials for lymphoma patients.