Abstract 3672: The three-dimensional (3D) spatial lamin A/C organization in normal lymphocytes, and in Hodgkin and Reed-Sternberg cells

Abstract

Abstract Classical Hodgkin Lymphoma (HL) is a B-Cell lymphoma comprising mononucleated Hodgkin cells (H) and diagnostic bi- to multi-nucleated Reed Sternberg cells (RS). Genomic instability in HL is characterized by telomere dysfunction caused by critically short telomeres and telomere uncapping. Super resolution microscopy showed significant increases in the amount of DNA-poor nuclear spaces in HL compared to normal primary lymphocytes. A direct 3D interaction between telomeres and shelterin protein TRF2 is progressively disrupted from H to RS cells by either massive upregulation or downregulation of TRF2. TRF2 interacts with nuclear matrix protein lamin A/C in the maintenance of the 3D genome organization, which is disturbed in H and RS cells. Therefore we hypothesized that the TRF2- telomere-lamin A/C interaction is also disturbed in H and RS cells and leads to organizational alterations of the genome in HL. To this end, we analyzed lamin A/C expression levels of lymphocytes, H and RS cells and found that lamin A/C is upregulated in cancer cells compared to both activated and resting lymphocytes. The regular homogeneous and round shaped pattern found in lymphocytes was replaced in H and RS cells by a more irregular one, characterized by the presence of lamin A/C invaginations and septa that subdivide the nuclei into multiple smaller compartments. Our data show no co-localization between telomeres and lamin A/C in the DNA-poor spaces. Lamin A/C bordered the DNA-poor spaces but was never found inside them or in association with inner telomere fragments. 3D TRF-2 staining showed upregulation of the protein compared to normal lymphocytes, in correlation with the observation made in EBV-negative patients with clinically aggressive disease. The analysis of pre-treatment Hodgkin's patients' samples will allow to determine whether the TRF2-telomere-lamin A/C binding is different in patients with recurrent versus non-recurrent disease. Citation Format: Fabio Contu, Aleksander Szczurek, Roberta Vanni, Hans Knecht, Sabine Mai. The three-dimensional (3D) spatial lamin A/C organization in normal lymphocytes, and in Hodgkin and Reed-Sternberg cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3672.