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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Research Article Hematology Oncology

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

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 1

Constitutive NOTCH1 activation boosts BM engraftment of human HSPCs and promotes ectopic T cell development.

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Constitutive NOTCH1 activation boosts BM engraftment of human HSPCs and ...
(A) Representative FACS phenotype of primary HSPCs from human CB (n = 5). (B) RAG-2–/– × γc–/– mice were transplanted with CD34+ CB HSPCs transduced with either retrovirus encoding ICN1 and GFP (ICN1; transduction efficiencies ± SEM: 21.0% ± 2.9%) or control retrovirus encoding GFP alone (GFP; 43.4% ± 8.2%). Shown are absolute numbers of human (CD45+) cells, normalized to 105 transduced input cells, in BM, spleen, and thymus at 9 weeks after transplant. (C) Percentages of human cells with the indicated cell phenotype recovered from the BM, spleen, and PB of mice shown in B. Percentages of cells derived from nontransduced (GFP–) HSPCs are also shown (SP T, CD4+ or CD8+ SP; DP T, CD4+CD8+ TCR-αβ+ DP; DP pre-T, CD4+CD8+ TCR-αβ–CD3lo; B, CD19+; Myeloid, CD33+CD13+; CD34+Lin–, CD34+ cells lacking lineage-specific markers). Mean values ± SEM are shown (n ≥ 4). (D) Representative phenotype of human cells derived from ICN1- or GFP-transduced HSPCs infiltrating the BM and thymus of mice shown in B (n ≥ 4). (E) Representative CD44 expression of human DP TCR-αβ+ and B cells from BM or thymus (Thy) of transplanted mice shown in B (n ≥ 6). (F) Percentages of human cells recovered at the indicated times after transplant from the PB of mice shown in B. Numbers were normalized to 25% of transduced input cells. Mean values from at least 4 independent experiments, with a combined total of 5 to 19 mice per group, are shown. ****P < 0.0001.