FBP1-Altered Carbohydrate Metabolism Reduces Leukemic Viability through Activating P53 and Modulating the...

Area of Science:

• Molecular Biology
• Cancer Metabolism
• Hematology

Background:

• Acute myeloid leukemia (AML) is a heterogeneous blood cancer with challenging relapse rates.
• Targeting metabolic homeostasis in leukemic cells is crucial for improving AML patient prognosis.
• Fructose-1,6-bisphosphatase 1 (FBP1) is a gluconeogenic enzyme that inhibits cancer cell glycolysis (Warburg effect) and its restoration can promote apoptosis in solid tumors.

Purpose of the Study:

• To investigate the anti-leukemic function of fructose-1,6-bisphosphatase 1 (FBP1) in acute myeloid leukemia (AML) cells.
• To explore FBP1 as a novel inducible therapeutic target in AML, particularly in subtypes with FLT3 mutations.

Main Methods:

• Generated a novel AML cell line (FBP1-MV4-11) by lentiviral overexpression of FBP1 in vitro.
• Compared apoptosis, proliferation, P53 expression, and mitochondrial homeostasis between FBP1-overexpressing and control AML cells.
• Utilized P53 promoter assays and supplementation with post-glycolytic metabolites for mechanistic investigation.

Main Results:

• FBP1-overexpressing AML cells (FBP1-MV4-11) exhibited increased susceptibility to apoptosis compared to control cells.
• FBP1 overexpression led to increased P53 gene and protein expression in AML blasts.
• Impaired mitochondrial homeostasis was observed in FBP1-MV4-11 cells, indicated by reduced COX2 and upregulated PINK1 expression.

Conclusions:

• This study provides the first in vitro evidence that FBP1 can induce leukemic cell death in AML blasts.
• FBP1-altered carbohydrate metabolism and FBP1-activated P53 initiate leukemic cell death via mitochondrial reprogramming.
• FBP1 represents a promising therapeutic target for AML and potentially other AML-like cancers.