Menin regulates the serine biosynthetic pathway in Ewing sarcoma

Area of Science:

• Oncology
• Epigenetics
• Cancer Metabolism

Background:

• Developmental transcription is epigenetically regulated by complexes like menin-MLL-containing trithorax (TrxG).
• In Ewing sarcoma, menin and MLL1 (lysine methyltransferase 2A, KMT2A) are overexpressed oncogenes.
• Inhibiting the menin-MLL interaction reduces Ewing sarcoma growth and tumorigenicity.

Purpose of the Study:

• Investigate the mechanistic basis of menin-MLL-mediated oncogenic activity in Ewing sarcoma.
• Determine the impact of menin-MLL inhibition on gene transcription and metabolic processes.
• Elucidate the role of the serine biosynthetic pathway (SSP) in Ewing sarcoma.

Main Methods:

• Bromouridine sequencing (Bru-seq) to assess nascent gene transcription changes.
• Treatment with menin-MLL interaction inhibitor MI-503.
• Loss of function studies and metabolic tracing with ¹³C-labeled glucose.

Main Results:

• Menin-MLL inhibition caused widespread reprogramming of metabolic processes, notably affecting the SSP.
• Ewing sarcoma exhibits high baseline expression and flux through the SSP, with PHGDH, PSAT1, and PSPH being key genes.
• Inhibition of PHGDH or menin reduced cell proliferation, viability, and tumor growth, and abrogated de novo serine and glycine biosynthesis.

Conclusions:

• The serine biosynthetic pathway (SSP) is highly active in Ewing sarcoma.
• Oncogenic activation of the SSP is maintained by menin-dependent epigenetic mechanisms involving TrxG complexes.
• Ewing sarcoma is critically dependent on the SSP for proliferation and survival.