Leukemia-expanded splenic CD81+ erythroblasts potentiate disease progression in mice by reshaping leukemic cell metabolism
Yue Li, Jiaxuan Cao, Jingyuan Tong, Peixia Tang, Haoran Chen, Guohuan Sun, Zining Yang, Xiaoru Zhang, Fang Dong, Shangda Yang, Jie Gao, Xiangnan Zhao, Jinfa Ma, Di Wang, Lei Zhang, Lin Wang, Tao Cheng, Hui Cheng, Lihong Shi
Yue Li, Jiaxuan Cao, Jingyuan Tong, Peixia Tang, Haoran Chen, Guohuan Sun, Zining Yang, Xiaoru Zhang, Fang Dong, Shangda Yang, Jie Gao, Xiangnan Zhao, Jinfa Ma, Di Wang, Lei Zhang, Lin Wang, Tao Cheng, Hui Cheng, Lihong Shi
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Research Article Cell biology Hematology Metabolism

Leukemia-expanded splenic CD81+ erythroblasts potentiate disease progression in mice by reshaping leukemic cell metabolism

Abstract

During the progression of acute myeloid leukemia (AML), extramedullary hematopoiesis (EMH) compensates for impaired bone marrow hematopoiesis. However, the specific cellular dynamics of EMH and its influence on AML progression remain poorly understood. In this study, we identified a substantial expansion of the CD81+ erythroblast subpopulation (CD81+ Erys) in the spleens of AML mice, which promoted AML cell proliferation and reduced survival. Mechanistically, CD81+ Erys secrete elevated levels of macrophage migration-inhibitory factor (MIF), which interacted with the CD74 receptor on AML cells, activating the mTORC1 signaling pathway and upregulating Egln3. Consequently, AML cells cocultured with CD81+ Erys exhibited reprogrammed phospholipid metabolism, characterized by an increased phospholipid-to-lysophospholipid ratio. Modulating this metabolic shift, either by supplementing exogenous lysophospholipids or depleting Egln3 in AML cells, restored the phospholipid balance and mitigated the protumorigenic effects induced by CD81+ Erys. Overall, our findings elucidate the molecular crosstalk between erythroblasts and AML cells, extend our insights into the mechanisms driving AML progression, and suggest potential therapeutic strategies.

Authors

Yue Li, Jiaxuan Cao, Jingyuan Tong, Peixia Tang, Haoran Chen, Guohuan Sun, Zining Yang, Xiaoru Zhang, Fang Dong, Shangda Yang, Jie Gao, Xiangnan Zhao, Jinfa Ma, Di Wang, Lei Zhang, Lin Wang, Tao Cheng, Hui Cheng, Lihong Shi

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Figure 3

CD81+ Erys promote AML cell proliferation and contribute to disease progression.

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CD81+ Erys promote AML cell proliferation and contribute to disease prog...
(A) A schematic illustrating the experimental design: AML cells were cocultured with total Erys, CD81− Erys, or CD81+ Erys isolated from the spleens of mice with advanced AML, or cultured alone, for 9 days. AML cell proliferation in each group was monitored, and cells were then collected for colony formation assays or injection into irradiated (4.5 Gy) mice. (B) Cell counts of AML cells obtained after 9 days of culture alone or coculture (n = 6). (C) Number of colonies formed by cultured AML cells (n = 4). (D and E) AML progression rates determined by the percentage of AML cells in mouse PB (D) and survival analysis (E) of mice i.v. injected with cultured AML cells (n = 8). Data are presented as the mean ± SEM. The results shown are representative of 1 of 3 independent experiments with consistent trends. **P < 0.01 and ***P < 0.001, by 1-way ANOVA (B–D) and log-rank test (E).