FGF11–HIF-1α glycolytic epigenetic axis drives AML progression and chemoresistance via metabolic reprogramming Free

BackgroundAcute myeloid leukemia (AML) remains a lethal hematologic malignancy characterized by clonal expansion of immature myeloid blasts and dismal long-term survival. Despite advances in genomics-guided therapy, relapse and chemoresistance are common, especially in older or refractory patients. Emerging evidence implicates metabolic reprogramming and bone marrow (BM) hypoxia as key drivers of leukemic stem cell (LSC) persistence and drug resistance. We previously identified FGF11—a member of the intracellular FGF subfamily—as markedly upregulated in primary AML blasts and cell lines. However, its mechanistic role in AML pathogenesis and therapeutic vulnerability remains undefined.MethodsWe analyzed FGF11 and HIF-1α expression in 173 de novo AML patient samples (TCGA-LAML and GTEx), 15 paired diagnosis/remission BM aspirates, and two AML cell lines (HL-60, HEL) using RNA-seq, qPCR, and immunohistochemistry. Subcellular localization and co-localization of FGF11 and HIF-1α were assessed by immunofluorescence and proximity ligation assays. Functional studies employed siRNA-mediated knockdown, and rhFGF11 supplementation. Seahorse metabolic flux analysis quantified glycolytic and oxidative phosphorylation (OXPHOS) rates. ResultsCompared with normal bone marrow, FGF11 mRNA was 4.3-fold higher in primary AML blasts (p<0.01) and predicted shorter event-free survival (EFS; HR=1.54, p=0.0028). Bioinformatic interrogation of the FGF11 promoter revealed hypomethylation at the CpG site cg00795277 that was tightly linked to adverse clinical outcomes, suggesting epigenetic activation of the locus.In HL-60 cells, immunofluorescence showed nuclear co-localization of FGF11 with HIF-1α, providing a spatial basis for functional interaction. Functional assays demonstrated that siRNA-mediated knockdown of FGF11 attenuated proliferation, enhanced apoptosis, and curtailed migration and invasion. Transcriptomic profiling of these cells disclosed down-regulation of HIF-1α signaling, alongside re-activation of mitochondrial and oxidative-phosphorylation programs, implying that FGF11 represses oxidative metabolism.To explore the reciprocal relationship, we exposed AML cells to CoCl2-induced hypoxia and observed a time-dependent increase in both FGF11 and HIF-1α mRNA and protein, confirming that HIF-1α can transcriptionally up-regulate FGF11. Proteomic analysis of hypoxic versus normoxic cells, annotated by COG classification, further enriched energy-metabolism pathway.Finally, exogenous rhFGF11 not only recapitulated the aggressive phenotype—enhancing migration and invasion—but also triggered a metabolic shift from oxidative phosphorylation to glycolysis. ConclusionsOur data uncover a novel FGF11–HIF-1α epigenetic-metabolic axis that orchestrates AML progression and chemoresistance through glycolytic reprogramming. Targeting this loop—either by disrupting FGF11/HIF-1α interaction or reversing metabolic addiction—represents a promising therapeutic strategy to overcome residual disease and improve outcomes in high-risk AML.