Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Hematology Oncology

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

  • Text
  • PDF
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

×

Figure 5

Constitutive Notch1 signaling promotes an aggressive human T-ALL.

Options: View larger image (or click on image) Download as PowerPoint
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.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts