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Exploitable metabolic dependencies in MLL-ENL-induced leukemia.

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Selective starvation targeting glucose and serine/glycine metabolism shows promise for leukemia treatment. Depriving leukemia cells of these nutrients selectively induces apoptosis, extending survival in preclinical models.

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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.