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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

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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 6

Coculturing with CD81+ Erys reshapes the metabolic profile of AML cells.

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Coculturing with CD81+ Erys reshapes the metabolic profile of AML cells....
(A) Module-trait correlations derived from weighted gene coexpression network analysis (WGCNA) of all expressed genes in AML cells that were either cultured alone or cocultured with CD81− Erys or CD81+ Erys and subsequently sequenced. KEGG analysis of genes in the blue and yellow modules was performed to identify the most significantly enriched pathways. The module eigengenes (ME) represent the overall gene expression profile. (B) Identification of metabolites specifically altered in AML cells cocultured with CD81+ Erys. Differential abundance was determined by comparing both CD81+ and CD81− Erys cocultures with AML monoculture. Selection criteria were set at a raw P value less than 0.05 and an FDR less than 0.2 for both comparisons. (C) Classification of differentially expressed metabolites identified in AML cells cocultured with CD81+ Erys using the ClassyFire superclass annotation. (D) Protein expression levels of LPCAT1, LPCAT3, and LPCAT4 in AML cells cultured alone or cocultured with CD81− Erys or CD81+ Erys. β-Actin was used as a loading control. Molecular weights are indicated on the right. (E) A schematic illustrating the experimental design for lysophosphatidylcholine (LysoPC) supplementation in AML monoculture. (F) Cell counts of AML cells obtained after 6 days of culture (n = 4). (G) Number of colonies formed by cultured AML cells (n = 4). (H) A schematic illustrating the experimental design: AML cells were cocultured with CD81− Erys or CD81+ Erys, or cultured alone, for 6 days, with or without LysoPC supplementation. (I) Cell counts of AML cells obtained after 6 days of culture (n = 5). Data are presented as the mean ± SEM. The results shown are representative of 1 of 3 independent experiments with consistent trends. ***P < 0.001, by 2-tailed, unpaired t test (F and G) and 1-way ANOVA (I).

Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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