TIFAB modulates metabolic pathways in KMT2A::MLLT3-induced AML through HNF4A

Blood Adv. 2025 Feb 25;9(4):844-855. doi: 10.1182/bloodadvances.2024013446.

Abstract

Tumor necrosis factor (TNF) receptor-associated factor (TRAF)-interacting protein with forkhead-associated domain B (TIFAB), an inhibitor of NF-κB signaling, plays critical roles in hematopoiesis, myelodysplastic neoplasms, and leukemia. We previously demonstrated that Tifab enhances KMT2A::MLLT3-driven acute myeloid leukemia (AML) by either upregulating Hoxa9 or through ubiquitin-specific peptidase 15-mediated downregulation of p53 signaling. In this study, we show that Tifab deletion in KMT2A::MLLT3-induced AML impairs leukemia stem/progenitor cell (LSPC) engraftment, glucose uptake, and mitochondrial function. Gene set enrichment analysis reveals that Tifab deletion downregulates MYC, HOXA9/MEIS1, mTORC1 signaling, and genes involved in glycolysis and oxidative phosphorylation. By comparing genes upregulated in TIFAB-overexpressing LSPCs with those downregulated upon Tifab deletion, we identify hepatocyte nuclear factor 4 alpha (Hnf4a) as a key TIFAB target, regulated through the inhibition of NF-κB component RelB, which suppresses Hnf4a in leukemia cells. HNF4A, a nuclear receptor involved in organ development, metabolism, and tumorigenesis, rescues the metabolic defects caused by Tifab deletion and enhances leukemia cell engraftment. Conversely, Hnf4a knockdown attenuates TIFAB-mediated enhancement of LSPC function. These findings highlight the critical role of the TIFAB-HNF4A axis in KMT2A::MLLT3-induced AML and uncover a novel regulator in leukemia biology.

MeSH terms

  • Animals
  • Gene Expression Regulation, Leukemic
  • Hepatocyte Nuclear Factor 4* / genetics
  • Hepatocyte Nuclear Factor 4* / metabolism
  • Histone-Lysine N-Methyltransferase* / genetics
  • Histone-Lysine N-Methyltransferase* / metabolism
  • Humans
  • Leukemia, Myeloid, Acute* / etiology
  • Leukemia, Myeloid, Acute* / genetics
  • Leukemia, Myeloid, Acute* / metabolism
  • Leukemia, Myeloid, Acute* / pathology
  • Metabolic Networks and Pathways*
  • Mice
  • Myeloid-Lymphoid Leukemia Protein* / genetics
  • Myeloid-Lymphoid Leukemia Protein* / metabolism
  • Signal Transduction

Substances

  • Myeloid-Lymphoid Leukemia Protein
  • Hepatocyte Nuclear Factor 4
  • Histone-Lysine N-Methyltransferase
  • KMT2A protein, human