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

Nature Medicine volume 23, pages 79–90 (2017)Cite this article

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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.

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Figure 1: Fasting selectively inhibits ALL development.
Figure 2: Fasting inhibits B-ALL development in both early and late stages.
Figure 3: Fasting upregulates LEPR expression and its downstream signaling.
Figure 4: Attenuated LEPR signaling is essential for ALL development, and fasting does not inhibit B-ALL development in the absence of LEPR.
Figure 5: LEPR inhibits B-ALL development by promoting leukemic cell differentiation through PRDM1.
Figure 6: Fasting and LEPR signaling inhibit human ALL development.

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Acknowledgements

We would like to acknowledge the support by grants from the US National Institutes of Health 1R01CA172268 (C.C.Z.), Leukemia & Lymphoma Society Awards 1024-14 (C.C.Z.) and TRP-6024-14 (C.C.Z.), CPRIT RP140402 (C.C.Z.), 1R01HL089966 (L.J.H.), R01-DK55758 (P.E.S.) and RP140412 (P.E.S.).

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Author notes

  1. Zhigang Lu and Jingjing Xie: These authors contributed equally to this work.

  2. zhigang.lu@utsouthwestern.edu

Authors and Affiliations

  1. Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Zhigang Lu, Jingjing Xie, Guojin Wu, Jinhui Shen, Xunlei Kang & Cheng Cheng Zhang

  2. BMU–UTSW Joint Taishan Immunology Group, Binzhou Medical University, Yantai, Shandong, China

    Jingjing Xie & Cheng Cheng Zhang

  3. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Robert Collins & Philipp E Scherer

  4. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Weina Chen

  5. Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Min Luo

  6. Department of Immunology, Central South University School of Xiangya Medicine, Changsha, Hunan, China

    Yizhou Zou

  7. Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Lily Jun-Shen Huang & Philipp E Scherer

  8. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    James F Amatruda, Tamra Slone & Naomi Winick

  9. Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Philipp E Scherer

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Contributions

C.C.Z. and Z.L. designed experiments. C.C.Z. conceived the study. Z.L., J.X., G.W., J.S. and P.E.S. performed experiments and interpreted data. L.J.-S.H., X.K., Y.Z. and M.L. performed experiments. Z.L. and J.X. performed statistical analysis. R.C., W.C., J.F.A., T.S. and N.W. provided patient samples. The manuscript was written by C.C.Z. and Z.L. and contributed to by all authors.

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Correspondence to Cheng Cheng Zhang.

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Lu, Z., Xie, J., Wu, G. et al. Fasting selectively blocks development of acute lymphoblastic leukemia via leptin-receptor upregulation. Nat Med 23, 79–90 (2017). https://doi.org/10.1038/nm.4252

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