1. Exploitable metabolic dependencies in MLL-ENL–induced leukemia
- Author
-
Markus Metzler, Robert K. Slany, Maria-Paz Garcia-Cuellar, Martin Böttcher, Dimitrios Mougiakakos, and Jennifer Lawlor
- Subjects
0301 basic medicine ,DNA damage ,PKM2 ,Heterogeneous-Nuclear Ribonucleoproteins ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Humans ,Protein Isoforms ,Glycolysis ,Cell Proliferation ,Leukemia ,Myeloid Neoplasia ,Chemistry ,Cell growth ,Glucose transporter ,Hematology ,medicine.disease ,Cell biology ,Transplantation ,030104 developmental biology ,030220 oncology & carcinogenesis ,Pyruvate kinase ,Polypyrimidine Tract-Binding Protein ,Transcription Factors - Abstract
Mixed-lineage leukemia (MLL) fusions are transcriptional activators that induce leukemia, with a dismal prognosis that mandates further elucidation of their transformation mechanism. In this study, knockdown of the direct MLL-ENL target gene polypyrimidine tract binding protein-1 (PTBP1) was rate limiting for cell proliferation and caused a metabolic phenotype associated with reduced glucose consumption and lactate production. This effect was accompanied by a reduction of splice isoform-2 of pyruvate kinase M (PKM2). Because PKM2 restricts glycolytic outflow to provide anabolic intermediates, we tested the consequences of glucose, energy, and Ser/Gly starvation for cell physiology. Administration of deoxyglucose, energetic decoupling with rotenone, and inhibition of Ser biosynthesis by CBR5884 had a significantly stronger influence on self-renewal and survival of transformed cells than on normal controls. In particular, inhibition of Ser synthesis, which branches off glycolysis caused accumulation of reactive oxygen species, DNA damage, and apoptosis, predominantly in leukemic cells. Depletion of exogenous Ser/Gly affected proliferation and self-renewal of murine and human leukemia samples, even though they are classified as nonessential amino acids. Response to Ser/Gly starvation correlated with glucose transport, but did not involve activation of the AMPK energy homeostasis system. Finally, survival times in transplantation experiments were significantly extended by feeding recipients a Ser/Gly-free diet. These results suggest selective starvation as an option for supportive leukemia treatment.
- Published
- 2020