Fasting Selectively Blocks Development of Acute Lymphoblastic Leukemia Via Leptin-receptor Upregulation

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2016 Dec 13

PMID 27941793

Citations 70

Authors

Zhigang Lu

Jingjing Xie

Guojin Wu

Jinhui Shen

Robert Collins

Weina Chen

Xunlei Kang

Min Luo

Yizhou Zou

Lily Jun-Shen Huang

James F Amatruda

Tamra Slone

Naomi Winick

Philipp E Scherer

Cheng Cheng Zhang

Affiliations

Soon will be listed here.

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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References

Nowak D, Stewart D, Koeffler H . Differentiation therapy of leukemia: 3 decades of development. Blood. 2009; 113(16):3655-65. PMC: 2943835. DOI: 10.1182/blood-2009-01-198911. View

Zheng J, Lu Z, Kocabas F, Bottcher R, Costell M, Kang X . Profilin 1 is essential for retention and metabolism of mouse hematopoietic stem cells in bone marrow. Blood. 2014; 123(7):992-1001. PMC: 3924932. DOI: 10.1182/blood-2013-04-498469. View

Myers Jr M, Leibel R, Seeley R, Schwartz M . Obesity and leptin resistance: distinguishing cause from effect. Trends Endocrinol Metab. 2010; 21(11):643-51. PMC: 2967652. DOI: 10.1016/j.tem.2010.08.002. View

Chen H, Charlat O, Tartaglia L, Woolf E, Weng X, Ellis S . Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell. 1996; 84(3):491-5. DOI: 10.1016/s0092-8674(00)81294-5. View

Park J, Kusminski C, Chua S, Scherer P . Leptin receptor signaling supports cancer cell metabolism through suppression of mitochondrial respiration in vivo. Am J Pathol. 2010; 177(6):3133-44. PMC: 2993284. DOI: 10.2353/ajpath.2010.100595. View

Weigle D, Duell P, Connor W, Steiner R, Soules M, Kuijper J . Effect of fasting, refeeding, and dietary fat restriction on plasma leptin levels. J Clin Endocrinol Metab. 1997; 82(2):561-5. DOI: 10.1210/jcem.82.2.3757. View

Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman J . Positional cloning of the mouse obese gene and its human homologue. Nature. 1994; 372(6505):425-32. DOI: 10.1038/372425a0. View

Ross J, Oeffinger K, Davies S, Mertens A, Langer E, Kiffmeyer W . Genetic variation in the leptin receptor gene and obesity in survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J Clin Oncol. 2004; 22(17):3558-62. DOI: 10.1200/JCO.2004.11.152. View

Ntziachristos P, Lim J, Sage J, Aifantis I . From fly wings to targeted cancer therapies: a centennial for notch signaling. Cancer Cell. 2014; 25(3):318-34. PMC: 4040351. DOI: 10.1016/j.ccr.2014.02.018. View

10.

Shi W, Liao Y, Willis S, Taubenheim N, Inouye M, Tarlinton D . Transcriptional profiling of mouse B cell terminal differentiation defines a signature for antibody-secreting plasma cells. Nat Immunol. 2015; 16(6):663-73. DOI: 10.1038/ni.3154. View

11.

Baskin D, Seeley R, Kuijper J, Lok S, Weigle D, Erickson J . Increased expression of mRNA for the long form of the leptin receptor in the hypothalamus is associated with leptin hypersensitivity and fasting. Diabetes. 1998; 47(4):538-43. DOI: 10.2337/diabetes.47.4.538. View

12.

Pietrocola F, Pol J, Vacchelli E, Rao S, Enot D, Baracco E . Caloric Restriction Mimetics Enhance Anticancer Immunosurveillance. Cancer Cell. 2016; 30(1):147-160. PMC: 5715805. DOI: 10.1016/j.ccell.2016.05.016. View

13.

Pramanik R, Sheng X, Ichihara B, Heisterkamp N, Mittelman S . Adipose tissue attracts and protects acute lymphoblastic leukemia cells from chemotherapy. Leuk Res. 2013; 37(5):503-9. PMC: 3622767. DOI: 10.1016/j.leukres.2012.12.013. View

14.

Sugihara E, Shimizu T, Kojima K, Onishi N, Kai K, Ishizawa J . Ink4a and Arf are crucial factors in the determination of the cell of origin and the therapeutic sensitivity of Myc-induced mouse lymphoid tumor. Oncogene. 2011; 31(23):2849-61. PMC: 3271180. DOI: 10.1038/onc.2011.462. View

15.

Weng A, Ferrando A, Lee W, Morris 4th J, Silverman L, Sanchez-Irizarry C . Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004; 306(5694):269-71. DOI: 10.1126/science.1102160. View

16.

Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando S, Iacobelli S . Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013; 369(2):111-21. DOI: 10.1056/NEJMoa1300874. View

17.

Fantuzzi G, Faggioni R . Leptin in the regulation of immunity, inflammation, and hematopoiesis. J Leukoc Biol. 2000; 68(4):437-46. View

18.

Coleman D, Hummel K . The influence of genetic background on the expression of the obese (Ob) gene in the mouse. Diabetologia. 1973; 9(4):287-93. DOI: 10.1007/BF01221856. View

19.

Bifulco M, Malfitano A . Comment on "the negative impact of being underweight and weight loss on survival of children with acute lymphoblastic leukemia.". Haematologica. 2015; 100(3):e118-9. PMC: 4349294. DOI: 10.3324/haematol.2014.122168. View

20.

Bordone L, Guarente L . Calorie restriction, SIRT1 and metabolism: understanding longevity. Nat Rev Mol Cell Biol. 2005; 6(4):298-305. DOI: 10.1038/nrm1616. View