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

Huizhong Xiong, Maicol Mancini, Michael Gobert, Shiqian Shen, Glaucia C. Furtado, Sergio A. Lira, Christopher N. Parkhurst, Veronique Garambois, Muriel Brengues, Carlos E. Tadokoro, Thomas Trimarchi, Gonzalo Gómez-López, Amartya Singh, Hossein Khiabanian, Sonia Minuzzo, Stefano Indraccolo, Camille Lobry, Iannis Aifantis, Daniel Herranz, Juan J. LafailleAntonio Maraver

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1594-1608
Number of pages15
JournalTheranostics
Volume11
Issue number4
DOIs
StatePublished - Jan 1 2021

All Science Journal Classification (ASJC) codes

  • Medicine (miscellaneous)
  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)

Keywords

  • DLL4
  • Demcizumab
  • Notch pathway
  • Patient-derived xenografts
  • T-ALL

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