(A) Venn diagram illustrates selection of 34 DEGs from AML cells after coculture with CD81⁺ Erys. DEGs were identified by intersecting those upregulated in AML cells cocultured with CD81⁺ Erys versus AML cells cocultured with CD81⁻ Erys (AML cells+CD81⁺ Erys vs. AML cells+CD81⁻ Erys) and compared with AML cells alone (AML cells+CD81⁺ Erys vs. AML cells); P_adj < 0.05. (B) Hallmark overrepresentation analysis of 34 DEGs. (C) Expression of 34 DEGs, including 6 core enrichment genes of mTORC1 signaling pathway (in red). (D) Illustration of experimental design: Egln3_CTRL or Egln3_OE AML cells were cultured alone or cocultured with Δ/Δ CD81⁺ Erys for 9 days. (E) Cell counts of AML cells obtained after 9 days of culture alone or coculture (n = 3). Egln3_CTRL AML cells cocultured with fl/fl CD81⁺ Erys were positive control. (F) Number of colonies formed by cultured AML cells (n = 4). (G and H) AML progression rates (determined by percentage of AML cells in mouse PB) (G) and survival analysis (H) of mice injected with cultured AML cells (n = 8). (I) Experimental design for coculturing nontarget control (NT) and Egln3_KO (Egln3_sg1, Egln3_sg2) AML cells with CD81⁺ Erys (top). Proliferation rates of NT and Egln3_KO AML cells were assessed after 6 days of culture alone or coculture with CD81⁺ Erys (n = 4) (bottom). Rates were calculated as the ratio of AML cell counts obtained after coculturing with CD81⁺ Erys to those obtained after culture alone. (J) Number of colonies formed by cultured AML cells (n = 4). (K and L) AML progression rates (determined by percentage of AML cells in mouse PB) (K) and survival analysis (L) of mice injected with cultured AML cells (n = 8). (M) Relative abundance of lysophospholipids and phospholipids in AML cells under different experimental conditions (n = 3). (N) Correlation between EGLN3 expression levels and disease outcomes in AML patient cohorts (GSE1159 and GSE6891; cutoff = median; figure generated using Kaplan-Meier Plotter; ref. 73). (O) Left: Infiltration of AML cells into spleen drives EMH and expansion of CD81⁺ Erys, fueling disease progression. Right: Molecular mechanism by which MIF, secreted by CD81⁺ Erys, interacts with CD74 on AML cells, activating mTORC1 pathway and upregulating downstream Egln3. This signaling cascade disrupts the metabolic balance between phospholipids and lysophospholipids, creating a favorable environment that supports AML cell proliferation, survival, and disease progression. Data are shown as the mean ± SEM. Results are representative of 1 of 3 independent experiments with consistent trends. *P < 0.05, **P < 0.01, and ***P < 0.001, by 1-way ANOVA (E–G, I–K, and M) or log-rank test (H, L, N).