The NOTCH1/CD44 axis drives pathogenesis in a T cell acute lymphoblastic leukemia model

• DOI: 10.1172/jci92981
• Publication Date: 2018-05-20T22:00:44Z
• Authors: Marina García-Peydró; Patricia Fuentes; Marta Mosquera; María J. García-León; Juan Alcain; Antonio Rodríguez; Purificación Garc...; Pablo Menéndez; Kees Weijer; Hergen Spits; David T. Scadden; Carlos Cuesta-Mateos; Cecilia Muñoz-Cal...; Francisco Sánchez...; María L. Toribio
• Keywords: Mice, Knockout; 0301 basic medicine; T cell development; Hematopoietic Stem Cell Transplantation; Hematology; Mice, SCID; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; 3. Good health; Mice; 03 medical and health sciences; Cell Transformation, Neoplastic; Hyaluronan Receptors; Oncology; Mice, Inbred NOD; Cell Line, Tumor; Leukemias; Mutation; Animals; Heterografts; Humans; Bone marrow; Receptor, Notch1; Neoplasm Transplantation; Signal Transduction

NOTCH1 is a prevalent signaling pathway in T cell acute lymphoblastic leukemia (T-ALL), but crucial NOTCH1 downstream signals and target genes contributing to T-ALL pathogenesis cannot be retrospectively analyzed in patients and thus remain ill defined. This information is clinically relevant, as initiating lesions that lead to cell transformation and leukemia-initiating cell (LIC) activity are promising therapeutic targets against the major hurdle of T-ALL relapse. Here, we describe the generation in vivo of a human T cell leukemia that recapitulates T-ALL in patients, which arises de novo in immunodeficient mice reconstituted with human hematopoietic progenitors ectopically expressing active NOTCH1. This T-ALL model allowed us to identify CD44 as a direct NOTCH1 transcriptional target and to recognize CD44 overexpression as an early hallmark of preleukemic cells that engraft the BM and finally develop a clonal transplantable T-ALL that infiltrates lymphoid organs and brain. Notably, CD44 is shown to support crucial BM niche interactions necessary for LIC activity of human T-ALL xenografts and disease progression, highlighting the importance of the NOTCH1/CD44 axis in T-ALL pathogenesis. The observed therapeutic benefit of anti-CD44 antibody administration in xenotransplanted mice holds great promise for therapeutic purposes against T-ALL relapse.