In vitro and in vivo modeling of helix-loop-helix protein-mediated reprogramming and malignanttransformation of lymphoid cells

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Oncogenic transformation is not only characterized by an enhanced proliferative capacity and/or higher apoptosis resistance of malignant cells, but also by a disruption of the physiological differentiation process. As a consequence, tumor cells can display features of lineage infidelity or even cellular reprogramming that might open up alternative growth and survival pathways. A number of lymphoid malignancies display a phenotype that is in accordance with such a reprogramming process, with classical Hodgkin lymphoma (cHL) being the most prominent example: in striking contrast to their origin from B-cells, the malignant Hodgkin-/Reed-Sternberg (HRS) cells of cHL have almost completely lost their B cell-specific gene expression program and have acquired the expression of genes characteristic for other hematopoietic lineages. In our previous work, we could demonstrate that functional inhibition of the B cell-associated helix-loop-helix transcription factor E2A by its antagonists ID2 and ABF1 represents a key event in this reprogramming process. In further work, we have generated Id2 and Abf1 transgenic mice, which show a profound disturbance of B cell differentiation, a phenotype that we consider as a first step towards an in vivo model of cHL. In addition, we have demonstrated that activation of B lineage-inappropriate signaling pathways, such as the LTR-driven expression of the myeloid CSF1 receptor, are required for growth and survival of HRS cells. In an extension of these findings, we plan to address the following topics in our current proposal: I) We will cross Id2 and Abf1 transgenic mice with mouse strains that carry key cHL-specific oncogenic defects driving growth and survival to promote the generation of a cHL in vivo model. II) We will analyze the capacity and the molecular action of lineage-inappropriate genes to induce reprogramming of B cells and to confer B cell receptor (BCR)-independent survival in the wild-type setting and in the context of reduced E2A activity. III) We will characterize the role of newly identified E2A target genes for malignant transformation of lymphoid cells in vitro and in vivo. Apart from insights into the (de)-differentiation and transformation process of lymphoid cells, our proposal seeks to identify new therapeutic targets for the treatment of human lymphomas, in particular for the growing number of human lymphomas with altered E2A activity.