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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 July 2, 2018; First published May 21, 2018
Citation Information: J Clin Invest. 2018;128(7):2802-2818. https://doi.org/10.1172/JCI92981.
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Categories: 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 5

Constitutive Notch1 signaling promotes an aggressive human T-ALL.

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Constitutive Notch1 signaling promotes an aggressive human T-ALL.
(A and...
(A and B) CB HSPCs transduced with ICN1 and GFP (7.4% ± 1.7%) were transplanted into NSG mice. Combined data from 4 independent experiments, with a total of 18 mice, are shown as percentages of human cells derived from nontransduced ICN1– (A) or ICN1-transduced (B) HSPCs engrafting the mouse BM at the indicated months after transplant. (C) Kaplan-Meier survival curves of mice shown in A and B. (D) Absolute numbers of human ICN1+ cells infiltrating the BM, spleen, thymus, and liver of diseased mice shown in B at 7 months after transplant. Data were normalized to 105 transduced input cells. Mean values combined from 4 independent experiments with 5 to 6 mice/group are shown. (E) Mean percentages ± SEM of human ICN1+ cells of the indicated cell subsets, as defined in Figure 1C, infiltrating the BM, spleen, and liver of diseased mice shown in B (n ≥ 3). (F) Representative phenotype of human ICN1+ cells infiltrating the BM and spleen of diseased mice shown in B (n ≥ 7). (G) Representative CD44 expression of human DP T cells derived from ICN1-transduced or nontransduced CB HSPCs, infiltrating the indicated organs of diseased mice shown in B (n ≥ 7). (H) Reverse-transcriptase PCR (RT-PCR) analysis of the TCR-Vβ repertoire of 3 samples of human ICN1+ DP T cells infiltrating the BM of diseased mice shown in B (bottom panels) at 7 months after transplant (n = 8). The polyclonal repertoire of DP thymocytes isolated from human postnatal thymus is shown as control (upper panel). ****P < 0.0001.
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