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 5

MIF plays a central role in mediating the AML-promoting effects of CD81+ Erys.

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MIF plays a central role in mediating the AML-promoting effects of CD81+...
(A) Illustration of experimental design (top) and cell counts (bottom) of AML cells cocultured with CD81+ Erys pretreated with either 10 μM 4-IPP or DMSO (n = 5). (B–D) Illustration of experimental design (B) for AML mouse model induction, flow cytometric sorting of CD81− Erys and CD81+ Erys from spleens of Miffl/fl (fl/fl) and EpoR-Cre;Miffl/fl (Δ/Δ) mice, and confirmation of Mif depletion by RT-qPCR (n = 3) (C) and ELISA (n = 4) (D). (E) Illustration of experimental design: AML cells were cocultured with fl/fl CD81− Erys, Δ/Δ CD81− Erys, fl/fl CD81+ Erys, or Δ/Δ CD81+ Erys, or cultured alone, for 9 days. AML cell proliferation in each group was monitored; then cells were collected for colony formation assays or injection into irradiated (4.5 Gy) mice. (F) Cell counts of AML cells obtained after 9 days of culture alone or coculture (n = 6). (G) Number of colonies formed by cultured AML cells (n = 4). (H and I) AML progression rates (determined by percentage of AML cells in mouse PB) (H) and survival analysis (I) of mice injected with cultured AML cells (n = 8). (J) Correlation between MIF expression levels and disease outcomes in AML patient cohorts (GSE1159 and GSE6891; cutoff = median; figure generated using Kaplan-Meier Plotter; ref. 73). (K) AML cells were assessed for the expression of CD74, CXCR2, and CXCR4 by flow cytometry. (L–O) Illustration of construction of nontarget control (NT) and Cd74_KO (Cd74_sg1, Cd74_sg2) AML cells, followed by measurement of CD74 expression by RT-qPCR (n = 3) (M) and flow cytometry (N), and assessment of proliferation rates of NT and Cd74_KO AML cells cocultured with or without CD81+ Erys (n = 4) (O). Rates were calculated as the ratio of AML cell counts obtained after coculturing with CD81+ Erys to those obtained after culture alone. Data represent the mean ± SEM. Results are representative of 1 of 3 independent experiments with consistent trends. **P < 0.01 and ***P < 0.001, by 1-way ANOVA (A, C, D, F, G, H, M, O) and log-rank test (I and J).