Fasting upregulates the leptin receptor (LEPR) to block development of B-ALL and T-ALL, but not AML.

  • Major finding: Fasting upregulates the leptin receptor (LEPR) to block development of B-ALL and T-ALL, but not AML.

  • Clinical relevance: LEPR is downregulated in ALL and reduced LEPR signaling correlates with short survival in patients.

  • Impact: Fasting has cancer type–dependent effects on leukemogenesis and may be beneficial in patients with ALL.

In some solid tumors, dietary restriction has been shown to enhance cancer prevention and treatment; however, the effects of dietary restriction in hematopoietic malignancies have not been determined. Lu, Xie, and colleagues investigated the effects of fasting on leukemia development using mouse models of B-cell acute lymphoblastic leukemia (B-ALL), T-cell acute lymphoblastic leukemia (T-ALL), and acute myeloid leukemia (AML). A fasting regimen consisting of six cycles of 1 day of fasting followed by 1 day of feeding blocked the development of both B-ALL and T-ALL and increased survival. However, fasting did not suppress AML development. In addition to inhibiting ALL initiation, fasting also suppressed the growth of ALL at later stages. Mechanistically, in ALL cells, but not AML cells, fasting upregulated the leptin receptor (LEPR), which activated downstream STAT3 and upregulated the transcription factor PRDM1 to promote differentiation. Further, loss of LEPR conferred resistance to fasting in mice with ALL, indicating that LEPR upregulation is responsible for the antileukemic effects of fasting, and PRDM1 loss prevented LEPR-induced B-ALL differentiation in vivo. Fasting also inhibited ALL development in a human xenograft model, suggesting that these results might translate to patients with ALL. In patients with leukemia, LEPR was expressed at comparable levels in normal bone marrow and patients with AML, but at lower levels in patients with B-ALL or T-ALL. Moreover, in patients with B-ALL, but not AML, expression of genes that negatively regulate or are negatively regulated by LEPR signaling were associated with poor outcome, suggesting that LEPR signaling is correlated with increased survival in patients with ALL. Overall, these findings demonstrate that fasting has cancer type–dependent effects on leukemia development, and suggest that fasting may induce cellular differentiation and improve survival in patients with B-ALL or T-ALL.

Lu Z, Xie J, Wu G, Shen J, Collins R, Chen W, et al. Fasting selectively blocks development of acute lymphoblastic leukemia via leptin-receptor upregulation. Nat Med 2016 Dec 12 [Epub ahead of print].

©2016 American Association for Cancer Research.
2016
American Association for Cancer Research.