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The NOTCH1/CD44 axis drives pathogenesis in a T cell acute lymphoblastic leukemia model
Marina García-Peydró, … , Francisco Sánchez-Madrid, María L. Toribio
Marina García-Peydró, … , Francisco Sánchez-Madrid, María L. Toribio
Published May 21, 2018
Citation Information: J Clin Invest. 2018;128(7):2802-2818. https://doi.org/10.1172/JCI92981.
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Research Article Hematology Oncology

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

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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.

Authors

Marina García-Peydró, Patricia Fuentes, Marta Mosquera, María J. García-León, Juan Alcain, Antonio Rodríguez, Purificación García de Miguel, Pablo Menéndez, Kees Weijer, Hergen Spits, David T. Scadden, Carlos Cuesta-Mateos, Cecilia Muñoz-Calleja, Francisco Sánchez-Madrid, María L. Toribio

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Figure 2

Human thymic precursors overexpressing active NOTCH1 undergo BM engraftment and extrathymic differentiation.

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Human thymic precursors overexpressing active NOTCH1 undergo BM engraftm...
(A) Representative phenotype of primary ETPs from human postnatal thymus (n = 20). (B and C) RAG-2–/– × γc–/– mice were transplanted with human ETPs transduced with ICN1 and GFP (19.3% ± 1.4% ICN1+) or GFP alone (28.0% ± 7.9% GFP+). Shown are absolute numbers of human cells recovered from thymus (B) and BM (C) at the indicated weeks after transplant. Numbers were normalized to 105 transduced input cells and represent combined results from 4 to 8 independent experiments, with a total of 35 to 75 mice per group. (D) Representative flow cytometry phenotype of human ICN1+ cells in BM and thymus of mice shown in B and C at 6 weeks after transplant (n = 4). (E) Representative CD44 expression of human DP TCR-αβ+ cells infiltrating the BM and thymus of mice shown in B and C (n ≥ 4). (F) Percentages of human CD45+ cells engrafting the BM of mice shown in B and C at the indicated times after transplant (n ≥4).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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