Abstract 671: Assessing the origins of anaplastic large cell lymphoma in murine models via forced lineage specificity of NPM-ALK expression in T cells

Abstract

Background: Anaplastic large cell lymphoma (ALCL) is a T cell lymphoma representing 10-15% of all childhood non Hodgkin lymphomas, whereby those positive for aberrant expression of Anaplastic Lymphoma kinase (ALK) account for 50-80% of cases. The oncogene Nucleophosmin 1 (NPM)-ALK is considered the main driver of pediatric ALCL identified in 83% of ALK+ cases. ALCL cells rarely express a T cell receptor (TCR), CD4 nor CD8 despite displaying an activated cytotoxic T cell phenotype (production of perforin and Granzyme B). Expression of NPM-ALK in mice from the T-cell specific CD4 promoter (which gives rise to expression throughout thymic development) gives rise to thymic lymphomas not mimicking human ALCL suggesting other events are required for peripheral T cell lymphoma development and/or expression of NPM-ALK at different stages of T cell progression: some theories have revolved around the possibility of an infectious aetiology, or subversion of the development of T cells within the thymus in the pathogenesis of ALCL. Objective: To assess the potential cell of origin of ALCL through lineage restriction of NPM-ALK to defined T cell lineages (CD4 or CD8) using TCR transgenic mice. Experimental procedure: Disease presentation following backcrossing of the CD4/NPM-ALK mouse to a clonal transgenic TCR OT1 (CD4/NPM-ALK/OTI) or OTII (CD4/NPM-ALK/OTII) genetic background in the presence and absence of RAG was monitored. The OTI and OTII transgenic mice express a transgenic TCR which is MHC class I restricted, with a CD8 or MHC class II with a CD4 developmental skew respectively. The TCR in these mice has been engineered to recognise ovalbumin peptides (ova). Results: CD4/NPM-ALK/OTI mice develop peripheral disease histopathologically mimicking human ALCL. Conversely, CD4/NPM-ALK/OTII mice develop cortical thymic lymphomas similar to the parental CD4/NPM-ALK strain and mostly of a CD4 single positive T cell phenotype (64%). Intriguingly, the peripheral T cell tumours that develop in the CD4/NPM-ALK/OTI mice do not express the transgenic OTI TCR (or endogenously rearranged TCR). Additionally, haemopoietic tumors only occur on a RAG competent genetic background or in the absence of ova stimulation even though TCR transgene expressing T cells are detected in the periphery of these mice (CD4/NPM-ALK/OTI + MHV-ova administration or CD4/NPM-ALK/OTI/RAG-/-). Conclusions: These data represent the first murine model resembling human ALCL and suggest that restriction of NPM-ALK to the CD8 T cell lineage results in a disease more closely resembling human ALCL. Furthermore, our data suggest that in the periphery, signaling though the TCR may be pejorative towards peripheral lymphoma development. Citation Format: Tim Malcolm, Camilla J. Fairbairn, Katherine Hughes, Lukas Kenner, Amos Burke, Suzanne Turner. Assessing the origins of anaplastic large cell lymphoma in murine models via forced lineage specificity of NPM-ALK expression in T cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 671.