Latexin deletion in the bone marrow niche suppresses leukemia via LIFR downregulation and immune activation
Cuiping Zhang, Xia Yao, Pinpin Sui, Liming Hou, Bowen Yan, Larry L. Luchsinger, Gang Huang, Sheng Tong, Youwen Zhang, Bojing Shao, Hong Qian, Hong Zheng, Hui Zhong, Feng-Chun Yang, Ying Liang
Cuiping Zhang, Xia Yao, Pinpin Sui, Liming Hou, Bowen Yan, Larry L. Luchsinger, Gang Huang, Sheng Tong, Youwen Zhang, Bojing Shao, Hong Qian, Hong Zheng, Hui Zhong, Feng-Chun Yang, Ying Liang
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Research Article Hematology Oncology

Latexin deletion in the bone marrow niche suppresses leukemia via LIFR downregulation and immune activation

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.

Authors

Cuiping Zhang, Xia Yao, Pinpin Sui, Liming Hou, Bowen Yan, Larry L. Luchsinger, Gang Huang, Sheng Tong, Youwen Zhang, Bojing Shao, Hong Qian, Hong Zheng, Hui Zhong, Feng-Chun Yang, Ying Liang

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Figure 5

Lxn–/– niche increases Cxcl9-mediated T cell accumulation.

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Lxn–/– niche increases Cxcl9-mediated T cell accumulation. (A) Percentag...
(A) Percentages (left panel) and absolute numbers (right panel) of CD8+ T cells in the BM of WT or Lxn–/– AML mice. Data are shown as mean ± SD for the indicated number of mice from 3 independent experiments. (B) Percentages (left panel) and absolute numbers (right panel) of CD4+ T cells in the BM of WT or Lxn–/– AML mice. Data are shown as mean ± SD for the indicated number of mice from 3 independent experiments. (C) PD-1 level (mean fluorescence intensity, MFI) in CD8+ T memory and effector cells (left panel) and representative flow cytometry profiles (right panel) in the BM of WT or Lxn–/– AML mice. Data are shown as mean ± SD for the indicated number of mice from a single experiment. (D) Cytokine array analysis of BM fluid from WT and Lxn–/– AML mice. Differentially expressed cytokines are highlighted (top panel). Quantification of signal intensities is shown on the bottom panel. Chemiluminescent signals were quantified using ImageJ after background subtraction and normalized to the internal positive control spots of each membrane. Relative expression was calculated by setting the WT group as 1. Data are shown as mean ± SD from a single experiment with a duplicate. (E) ELISA of CXCL9 in the BM fluid of WT and Lxn–/– AML mice. Data are shown as mean ± SD for the indicated number of mice from a single experiment. (F) H3K27me3 binding at the Cxcl9 promoter region (UCSC Genome Browser, top panel). Schematic of primers used for ChIP-qPCR (middle panel). ChIP-qPCR using an H3K27me3 antibody shows reduced H3K27me3 occupancy at the Cxcl9 promoter in Lxn–/– MSCs compared with WT MSCs (bottom panel). IgG served as a negative control. Data are shown as mean ± SD for the indicated number of samples from a single experiment. A 2-tailed, unpaired Student’s t test was performed. *P < 0.05, **P < 0.01, ***P < 0.001.