Fasting selectively blocks development of acute lymphoblastic leukemia via leptin-receptor upregulation

Nat Med. 2017 Jan;23(1):79-90. doi: 10.1038/nm.4252. Epub 2016 Dec 12.

Abstract

New therapeutic approaches are needed to treat leukemia effectively. Dietary restriction regimens, including fasting, have been considered for the prevention and treatment of certain solid tumor types. However, whether and how dietary restriction affects hematopoietic malignancies is unknown. Here we report that fasting alone robustly inhibits the initiation and reverses the leukemic progression of both B cell and T cell acute lymphoblastic leukemia (B-ALL and T-ALL, respectively), but not acute myeloid leukemia (AML), in mouse models of these tumors. Mechanistically, we found that attenuated leptin-receptor (LEPR) expression is essential for the development and maintenance of ALL, and that fasting inhibits ALL development by upregulation of LEPR and its downstream signaling through the protein PR/SET domain 1 (PRDM1). The expression of LEPR signaling-related genes correlated with the prognosis of pediatric patients with pre-B-ALL, and fasting effectively inhibited B-ALL growth in a human xenograft model. Our results indicate that the effects of fasting on tumor growth are cancer-type dependent, and they suggest new avenues for the development of treatment strategies for leukemia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Line, Tumor
  • Computer Simulation
  • Disease Models, Animal
  • Fasting / metabolism*
  • Flow Cytometry
  • Humans
  • Leukemia, Myeloid, Acute / metabolism*
  • Mice
  • Mice, SCID
  • Neoplasm Transplantation
  • Positive Regulatory Domain I-Binding Factor 1
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
  • Prognosis
  • Real-Time Polymerase Chain Reaction
  • Receptors, Leptin / genetics
  • Receptors, Leptin / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factors / metabolism*
  • Up-Regulation

Substances

  • Prdm1 protein, mouse
  • Receptors, Leptin
  • Transcription Factors
  • leptin receptor, human
  • Positive Regulatory Domain I-Binding Factor 1