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

Area of Science:

• Oncology
• Molecular Biology
• Hematology

Background:

• Tumor necrosis factor (TNF) receptor-associated factor (TRAF)-interacting protein with forkhead-associated domain B (TIFAB) is an NF-κB signaling inhibitor involved in hematopoiesis and leukemia.
• TIFAB was previously shown to enhance KMT2A::MLLT3-driven acute myeloid leukemia (AML) by upregulating Hoxa9 or downregulating p53 signaling.

Purpose of the Study:

• To investigate the role of TIFAB in KMT2A::MLLT3-induced AML, focusing on its impact on leukemia stem/progenitor cell (LSPC) function and metabolism.
• To identify key downstream targets of TIFAB in AML pathogenesis.

Main Methods:

• Tifab deletion in a mouse model of KMT2A::MLLT3-induced AML.
• Analysis of LSPC engraftment, glucose uptake, and mitochondrial function.
• Gene set enrichment analysis (GSEA) to identify downregulated pathways.
• Comparison of gene expression profiles between TIFAB-overexpressing and Tifab-deleted LSPCs.
• Functional rescue experiments using hepatocyte nuclear factor 4 alpha (Hnf4a).

Main Results:

• Tifab deletion impaired LSPC engraftment, glucose uptake, and mitochondrial function in KMT2A::MLLT3-induced AML.
• Tifab deletion led to downregulation of MYC, HOXA9/MEIS1, mTORC1 signaling, glycolysis, and oxidative phosphorylation genes.
• Hepatocyte nuclear factor 4 alpha (Hnf4a) was identified as a key TIFAB target, regulated by NF-κB component RelB.
• HNF4A expression rescued metabolic defects and enhanced LSPC engraftment caused by Tifab deletion.
• Hnf4a knockdown attenuated TIFAB-mediated enhancement of LSPC function.

Conclusions:

• The TIFAB-HNF4A axis is critical for KMT2A::MLLT3-induced AML pathogenesis.
• TIFAB promotes AML by regulating LSPC metabolism and engraftment through HNF4A.
• This study uncovers a novel regulator in leukemia biology with potential therapeutic implications.