Exploitable metabolic dependencies in MLL-ENL-induced leukemia

Area of Science:

• Oncology
• Molecular Biology
• Metabolic Pathways

Background:

• Mixed-lineage leukemia (MLL) fusions drive oncogenesis with poor prognosis.
• Understanding MLL-driven leukemia transformation mechanisms is critical for new therapies.

Purpose of the Study:

• To investigate the role of polypyrimidine tract binding protein-1 (PTBP1) in MLL-driven leukemia.
• To explore the metabolic vulnerabilities of leukemia cells, particularly concerning glucose and serine/glycine metabolism.

Main Methods:

• Knockdown of PTBP1 to assess its impact on cell proliferation and metabolism.
• Utilized metabolic inhibitors (deoxyglucose, rotenone) and biosynthesis inhibitors (CBR5884).
• Assessed effects of serine/glycine starvation on leukemia cell lines and primary samples, including transplantation experiments.

Main Results:

• PTBP1 knockdown impaired proliferation and altered glucose metabolism, reducing pyruvate kinase M isoform 2 (PKM2) activity.
• Inhibition of glucose, energy, or serine biosynthesis selectively impacted leukemia cell survival and self-renewal.
• Serine synthesis inhibition induced reactive oxygen species, DNA damage, and apoptosis in leukemic cells.
• Serine/glycine depletion affected leukemia cell proliferation and self-renewal, independent of AMPK activation.
• A serine/glycine-free diet significantly extended survival in leukemia transplantation models.

Conclusions:

• Selective starvation, particularly of serine/glycine, represents a potential therapeutic strategy for leukemia.
• Targeting metabolic pathways offers a novel approach to combat MLL-driven leukemias.
• Further research into metabolic dependencies could lead to improved supportive care for leukemia patients.