PRE‐T CELL RECEPTOR SIGNALING DRIVES LEUKEMOGENESIS AND IS A THERAPEUTIC TARGET IN T CELL ACUTE LYMPHOBLASTIC LEUKEMIA

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive lymphoid neoplasm that results from the malignant transformation of T-cell progenitors. The biology of T-ALL is strongly influenced by its developmental origins. For example, mutations in NOTCH1, a critical regulator of thymocyte development, are found in approximately 60% of patient tumors. Less is known, however, about the extent to which other determinants of thymocyte development participate in the leukemogenesis of T-ALL. Using a thymus transplantation-based, spontaneous mouse model of T-ALL, we found that multiple β-selection checkpoint factors were upregulated in leukemic T cells, including Ptcra, a subunit of the pre-T cell receptor (pre-TCR) complex. Genetic ablation of Ptcra in the mouse model dramatically reduced the occurrence of T-ALL. In human T-ALL cell lines, CRISPR/Cas9 knockout of PTCRA reduced in vitro proliferative capacity and the ability to form tumors in vivo. Analysis of clinical T-ALL datasets and patient samples demonstrated that PTCRA is highly and specifically expressed in leukemic T cells but not in normal, mature T cells, suggesting an appropriate therapeutic window for targeted therapy in T-ALL. Cumulatively, our findings highlight an important role for pre-TCR signaling in driving and sustaining T-ALL and support the further evaluation of PTCRA-directed therapies in T-ALL. Keywords: Notch pathway; T-cells. Disclosures: Kuhnert, F: Employment Leadership Position: Regeneron Pharmaceuticals Inc.