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

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 8

CD44-mediated interaction with the BM microenvironment is required for T-ALL cell leukemogenesis.

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CD44-mediated interaction with the BM microenvironment is required for T...
(A) NSG mice transplanted with primary T-ALL2 cells received 3 weekly i.p. injections of either blocking anti-CD44 mAb (HP2/9) or control IgG1 during 7 weeks, starting at 1 week after transplant. (B) Image of representative spleens obtained at the end of treatment from mice shown in A. (C) Percentages of T-ALL2 cells infiltrating the BM, PB, and spleen of 5 to 10 mice treated as shown in A. (D) Representative FACS analysis showing persistence of anti-CD44 HP2/9 mAb on the surface of T-ALL cells recovered from the BM of NSG mice represented in A at the end of treatment with either anti-CD44 mAb or IgG1. Bound HP2/9 mAb was detected by reactivity with PE-labeled anti-mouse IgG1 (n = 3). (E) FACS analysis showing levels of HP2/9 anti-CD44 mAb persisting on the surface of T-ALL2 cells that infiltrate the BM of anti-CD44–treated mice shown in A at the indicated weeks after transplant. Shown are MFI values from a total of 7 mice, determined as in D. (F) BM and PB infiltration of T-ALL1 cells transduced with a lentiviral vector encoding GFP and either CD44-specific shRNA (28% transduction efficiency) or a scramble control shRNA (36%). Data show percentages of GFP+ cells within infiltrating CD45+ T-ALL1 cells of 5 NSG mice/group at 11 weeks after transplant. *P < 0.05; **P < 0.01; ****P < 0.0001.