IL-2 and IL-15 blockade by BNZ-1, an inhibitor of selective γ-chain cytokines, decreases leukemic T-cell viability.

Abstract

Interleukin-15 (IL-15) and IL-2 drive T-cell malignancies including T-cell large granular lymphocyte leukemia (T-LGLL) and HTLV-1 driven adult T-cell leukemia (ATL). Both cytokines share common γ-chain receptors and downstream signaling pathways. T-LGLL is characterized by clonal expansion of cytotoxic T cells and is associated with abnormal JAK/STAT signaling. ATL is an aggressive CD4+ T-cell neoplasm associated with HTLV-1. T-LGLL and ATL share dependence on IL-2 and IL-15 for survival and both diseases lack effective therapies. BNZ-1 is a pegylated peptide designed to specifically bind the γc receptor to selectively block IL-2, IL-15, and IL-9 signaling. We hypothesized that treatment with BNZ-1 would reduce cytokine-mediated proliferation and viability. Our results demonstrated that in vitro treatment of a T-LGLL cell line and ex vivo treatment of T-LGLL patient cells with BNZ-1 inhibited cytokine-mediated viability. Furthermore, BNZ-1 blocked downstream signaling and increased apoptosis. These results were mirrored in an ATL cell line and in ex vivo ATL patient cells. Lastly, BNZ-1 drastically reduced leukemic burden in an IL-15-driven human ATL mouse xenograft model. Thus, BNZ-1 shows great promise as a novel therapy for T-LGLL, ATL, and other IL-2 or IL-15 driven hematopoietic malignancies.

• Authors: T Tiffany Wang, Jun Yang, Yong Zhang, Meili Zhang, Sigrid Dubois, Kevin C Conlon, Yutaka Tagaya, Cait E Hamele, Shubha Dighe, Thomas L Olson, David J Feith, Nazli Azimi, Thomas A Waldmann, Thomas P Loughran Jr
• Journal: Leukemia (Leukemia) Vol. 33 Issue 5 Pg. 1243-1255 (05 2019) ISSN: 1476-5551 [Electronic] England
• PMID: 30353031 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• 7-chloro-4-(cyclohexylmethyl)-1-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione
• Annexin A5
• Cytokines
• Interleukin-15
• Interleukin-2
• STAT Transcription Factors
• Benzodiazepines
• Janus Kinases

Topics

• Animals
• Annexin A5 (metabolism)
• Apoptosis (drug effects)
• Benzodiazepines (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cytokines (metabolism)
• Disease Models, Animal
• Humans
• Interleukin-15 (antagonists & inhibitors)
• Interleukin-2 (antagonists & inhibitors)
• Janus Kinases (metabolism)
• Leukemia, T-Cell (metabolism)
• Mice
• Phosphorylation
• STAT Transcription Factors (metabolism)
• Signal Transduction (drug effects)