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 2

Lxn deletion in niche attenuates MLL-AF9–induced (MA9-induced) leukemia development.

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Lxn deletion in niche attenuates MLL-AF9–induced (MA9-induced) leukemia ...
(A) Schematic diagram of MLL-AF9–induced AML development via retroviral transduction and transplantation into WT and Lxn–/– recipient mice. (B) Kaplan-Meier survival curves of AML mice in Lxn–/– or WT recipient mice. Statistical significance was determined using the log-rank (Mantel-Cox) test. (C) GFP+ leukemic blast percentages in peripheral blood (PB) of AML WT or Lxn–/– recipient mice. Data are shown as mean ± SD for the indicated number of mice from 2 independent experiments. (D and E) Absolute number of leukemic stem cells (LSCs), identified as L-GMPs, in the PB and BM of AML WT or Lxn–/– recipient mice. Data are shown as mean ± SD for the indicated number of mice from 3 independent experiments. (F) Kaplan-Meier survival curves of AML developed in the control, Nes-Cre; Lxn loxp/loxp, or Osx-Cre; Lxn loxp/loxp conditional KO recipient mice. Overall differences were analyzed using the log-rank (Mantel-Cox) test, followed by pairwise comparisons with Holm-Šídák correction for multiple testing. (G) GFP+ leukemic blast percentages in PB of AML developed in the control, Nes-Cre; Lxn loxp/loxp, or Osx-Cre; Lxn loxp/loxp conditional KO recipient mice. Data are shown as mean ± SD for the indicated number of mice from a single experiment. A 2-tailed, unpaired Student’s t test was performed in C–E. One-way ANOVA was used for comparisons among multiple groups in G. *P < 0.05, **P < 0.01.