Latexin deletion in the bone marrow niche suppresses leukemia via LIFR downregulation and immune activation
8 affiliations
- 1Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky, USA.
- 2Lindsley F. Kimball Research Institute, New York Blood Center, Rye, New York, USA.
- 3Department of Cell Systems & Anatomy, University of Texas Health at San Antonio, San Antonio, Texas, USA.
- 4Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida, USA.
- 5Department of Bioengineering, University of Kentucky, Lexington, Kentucky, USA.
- 6Center for Computational and Integrative Biology, Rutgers University-Camden, Camden, New Jersey, USA.
- 7Karolinska Institute, Flemingsberg Campus, Huddinge, Sweden.
- 8Division of Hematology/Oncology, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
Abstract
Acute myeloid leukemia (AML) is the most common adult leukemia diagnosis. Bone marrow (BM) niche significantly influences the initiation and progression of AML. However, our knowledge about the effect of leukemic niche on leukemia stem cells (LSC) and leukemogenesis is limited. In this study, we identified an extrinsic-regulatory function of latexin (Lxn) in leukemogenesis. Using a MLL-AF9–induced AML mouse model in WT and Lxn-KO (Lxn–/–) recipient mice, we found that Lxn deletion in the BM niche enhanced the survival of AML mice by suppressing LSCs and reducing blood blasts. Single-cell RNA-seq of stromal cells and cell communication analysis uncovered downregulation of the leukemia inhibitory factor receptor (LIFR) signaling pathway in the Lxn–/– niche, particularly within mesenchymal stromal cells (MSCs). Mechanistically, reduced LIFR level in Lxn–/– MSCs upregulated Cxcl9 expression, leading to increased recruitment of CD8 T cells and enhanced cytotoxicity against leukemic cells. Combination of Lxn niche deletion and immune checkpoint inhibitor PD-1 further prolonged survival. The findings have important clinical implications, suggesting that Lxn inhibition could improve the efficacy of AML therapies by targeting the leukemia niche and enhancing immune surveillance.
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BibTeX
@article{zhang2026latexin,
title = {{Latexin deletion in the bone marrow niche suppresses leukemia via LIFR downregulation and immune activation}},
author = {Cuiping Zhang and Xia Yao and Pinpin Sui and Liming Hou and Bowen Yan and Larry L. Luchsinger and Gang Huang and Sheng Tong and Youwen Zhang and Bojing Shao and Hong Qian and Hong Zheng and Hui Zhong and Feng-Chun Yang and Ying Liang},
journal = {JCI Insight},
year = {2026},
month = oct,
doi = {10.1172/jci.insight.199771},
url = {https://doi.org/10.1172/jci.insight.199771},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Latexin deletion in the bone marrow niche suppresses leukemia via LIFR downregulation and immune activation
AU - Cuiping Zhang
AU - Xia Yao
AU - Pinpin Sui
AU - Liming Hou
AU - Bowen Yan
AU - Larry L. Luchsinger
AU - Gang Huang
AU - Sheng Tong
AU - Youwen Zhang
AU - Bojing Shao
AU - Hong Qian
AU - Hong Zheng
AU - Hui Zhong
AU - Feng-Chun Yang
AU - Ying Liang
PY - 2026
DA - 2026/10/08
JO - JCI Insight
DO - 10.1172/jci.insight.199771
UR - https://doi.org/10.1172/jci.insight.199771
AB - Acute myeloid leukemia (AML) is the most common adult leukemia diagnosis. Bone marrow (BM) niche significantly influences the initiation and progression of AML. However, our knowledge about the effect of leukemic niche on leukemia stem cells (LSC) and leukemogenesis is limited. In this study, we identified an extrinsic-regulatory function of latexin (Lxn) in leukemogenesis. Using a MLL-AF9–induced AML mouse model in WT and Lxn-KO (Lxn–/–) recipient mice, we found that Lxn deletion in the BM niche enhanced the survival of AML mice by suppressing LSCs and reducing blood blasts. Single-cell RNA-seq of stromal cells and cell communication analysis uncovered downregulation of the leukemia inhibitory factor receptor (LIFR) signaling pathway in the Lxn–/– niche, particularly within mesenchymal stromal cells (MSCs). Mechanistically, reduced LIFR level in Lxn–/– MSCs upregulated Cxcl9 expression, leading to increased recruitment of CD8 T cells and enhanced cytotoxicity against leukemic cells. Combination of Lxn niche deletion and immune checkpoint inhibitor PD-1 further prolonged survival. The findings have important clinical implications, suggesting that Lxn inhibition could improve the efficacy of AML therapies by targeting the leukemia niche and enhancing immune surveillance.
SN - 2379-3708
ER -