LAIR-1 agonism as a therapy for acute myeloid leukemia
Authors:
- Rustin R. LovewellRLRustin R. Lovewell
- Junshik HongJHJunshik Hong
- Subhadip KunduSKSubhadip Kundu
- Carly M. FielderCFCarly M. Fielder
- Qianni HuQHQianni Hu
- Haley E. RamseyHRHaley E. Ramsey
- Agnieszka E. GorskaAGAgnieszka E. Gorska
- Linjie TianLTLinjie Tian
- Priyanka KothariPKPriyanka Kothari
- Ana PaucarmaytaAPAna Paucarmayta
Open Access
- 15 November 2023
- journal article
- research article
- Published by American Society for Clinical Investigation in Journal of Clinical Investigation
- Vol. 133 (22)
Abstract
Effective eradication of leukemic stem cells (LSCs) remains the greatest challenge in treating acute myeloid leukemia (AML). The immune receptor LAIR-1 has been shown to regulate LSC survival; however, the therapeutic potential of this pathway remains unexplored. We developed a therapeutic LAIR-1 agonist antibody, NC525, that induced cell death of LSCs, but not healthy hematopoietic stem cells in vitro, and killed LSCs and AML blasts in both cell- and patient-derived xenograft models. We showed that LAIR-1 agonism drives a unique apoptotic signaling program in leukemic cells that was enhanced in the presence of collagen. NC525 also significantly improved the activity of azacitidine and venetoclax to establish LAIR-1 targeting as a therapeutic strategy for AML that may synergize with standard-of-care therapies.Keywords
This publication has 36 references indexed in Scilit:
- Inhibitory leukocyte immunoglobulin-like receptors: Immune checkpoint proteins and tumor sustaining factorsCell Cycle, 2016
- Antileukemic activity of nuclear export inhibitors that spare normal hematopoietic cellsLeukemia, 2012
- Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with ageProceedings of the National Academy of Sciences, 2011
- The Collagen FamilyCold Spring Harbor Perspectives in Biology, 2010
- Hematopoietic stem cell: self‐renewal versus differentiationWIREs Mechanisms of Disease, 2010
- LAIR and collagens in immune regulationImmunology Letters, 2010
- The inhibitory collagen receptor LAIR-1 (CD305)Journal of Leukocyte Biology, 2007
- Mouse leukocyte-associated Ig-like receptor-1 (mLAIR-1) functions as an inhibitory collagen-binding receptor on immune cellsInternational Immunology, 2007
- Collagens are functional, high affinity ligands for the inhibitory immune receptor LAIR-1Journal of Experimental Medicine, 2006
- Leukocyte‐associated Ig‐like receptor‐1 has SH2 domain‐containing phosphatase‐independent function and recruits C‐terminal Src kinaseEuropean Journal of Immunology, 2005