Spleen plays a major role in DLL4-driven acute T-cell lymphoblastic leukemia

Theranostics. 2021 Jan 1;11(4):1594-1608. doi: 10.7150/thno.48067.

Huizhong Xiong ¹ ² ³, Maicol Mancini ⁴, Michael Gobert ¹, Shiqian Shen ¹ ⁵, Glaucia C Furtado ⁶, Sergio A Lira ⁶, Christopher N Parkhurst ¹, Veronique Garambois ⁴, Muriel Brengues ⁴, Carlos E Tadokoro ¹ ⁷, Thomas Trimarchi ⁸, Gonzalo Gómez-López ⁹, Amartya Singh ¹⁰, Hossein Khiabanian ¹⁰ ¹¹, Sonia Minuzzo ¹², Stefano Indraccolo ¹³, Camille Lobry ⁸ ¹⁴, Iannis Aifantis ⁸ ¹⁵, Daniel Herranz ¹⁰ ¹⁶, Juan J Lafaille ¹ ⁸, Antonio Maraver ⁴

Affiliations

1 Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA.
2 The Sackler Institute of Graduate Biomedical Sciences, New York University School of Medicine, New York, NY 10016, USA.
3 Current address: Genentech, South San Francisco, CA, 94080.
4 Institut de Recherche en Cancérologie de Montpellier (IRCM), Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier, 34298, Cedex 5, France.
5 Current address: Department of Anesthesia, Critical Care and Pain Medicine Massachusetts General Hospital, Boston, MA 02114, USA.
6 Immunology Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
7 Current address: Universidade Vila Velha, Vila Velha, 29102-920, Brazil.
8 Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
9 Bioinformatics unit. Spanish National Cancer Research Center (CNIO). Madrid, Spain.
10 Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, USA.
11 Department of Pathology and Laboratory Medicine, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA.
12 Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
13 Veneto Institute of Oncology IOV - IRCCS, Padova, Italy.
14 Institut de Recherche Saint Louis, INSERM U944/CNRS UMR7212, Paris, 75010, France.
15 Howard Hughes Medical Institute.
16 Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, USA.

PMID: 33408769 DOI: 10.7150/thno.48067

Abstract

The Notch pathway is highly active in almost all patients with T-cell acute lymphoblastic leukemia (T-ALL), but the implication of Notch ligands in T-ALL remains underexplored. Methods: We used a genetic mouse model of Notch ligand delta like 4 (DLL4)-driven T-ALL and performed thymectomies and splenectomies in those Animals. We also used several patient-derived T-ALL (PDTALL) models, including one with DLL4 expression on the membrane and we treated PDTALL cells in vitro and in vivo with demcizumab, a blocking antibody against human DLL4 currently being tested in clinical trials in patients with solid Cancer. Results: We show that surgical removal of the spleen abrogated T-ALL development in our preclinical DLL4-driven T-ALL mouse model. Mechanistically, we found that the spleen, and not the thymus, promoted the accumulation of circulating CD4⁺CD8⁺ T cells before T-ALL onset, suggesting that DLL4-driven T-ALL derives from these cells. Then, we identified a small subset of T-ALL patients showing higher levels of DLL4 expression. Moreover, in mice xenografted with a DLL4-positive PDTALL model, treatment with demcizumab had the same therapeutic effect as global Notch pathway inhibition using the potent γ-secretase Inhibitor dibenzazepine. This result demonstrates that, in this PDTALL model, Notch pathway activity depends on DLL4 signaling, thus validating our preclinical mouse model. Conclusion: DLL4 expression in human leukemic cells can be a source of Notch activity in T-ALL, and the spleen plays a major role in a genetic mouse model of DLL4-driven T-ALL.

Keywords

DLL4; Notch pathway; T-ALL; demcizumab; patient-derived xenografts.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-P99261

Demcizumab

anti-DLL4 mAb

Notch

Cancer

Name
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