The NOTCH1/CD44 axis drives pathogenesis in a T cell acute lymphoblastic leukemia model
Open Access
- 21 May 2018
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 128 (7), 2802-2818
- https://doi.org/10.1172/jci92981
Abstract
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.Funding Information
- Ministerio de Economía y Competitividad y Fondo Europeo de Desarrollo Regional (MINECO/FEDER) (PLE-2009-0110)
- Ministerio de Economía y Competitividad y Fondo Europeo de Desarrollo Regional (MINECO/FEDER) (SAF2013-44857-R)
- Ministerio de Economía y Competitividad y Fondo Europeo de Desarrollo Regional (MINECO/FEDER) (SAF2016-75442-R)
- Fundación Sandra Ibarra (FSI-2011-012)
- Fundación Asociación Española Contra el Cáncer (AECC) (CI13131229)
- Instituto de Salud Carlos III (RTICC RD06/0014/1012)
- Fundación Ramón Areces (Institutional Grant)
- 7th Framework Program of the European Union ((FP7-HEALTH-2013-INNOVATION-1-602587))
- Banco de Santander (Institutional Grant)
- Ministerio de Economía y Competitividad y Fondo Europeo de Desarrollo Regional (MINECO/FEDER) (SAF2010-15106)
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