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

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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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          Most cited references 37

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          Acute lymphoblastic leukaemia.

          Acute lymphoblastic leukaemia occurs in both children and adults but its incidence peaks between 2 and 5 years of age. Causation is multifactorial and exogenous or endogenous exposures, genetic susceptibility, and chance have roles. Survival in paediatric acute lymphoblastic leukaemia has improved to roughly 90% in trials with risk stratification by biological features of leukaemic cells and response to treatment, treatment modification based on patients' pharmacodynamics and pharmacogenomics, and improved supportive care. However, innovative approaches are needed to further improve survival while reducing adverse effects. Prognosis remains poor in infants and adults. Genome-wide profiling of germline and leukaemic cell DNA has identified novel submicroscopic structural genetic changes and sequence mutations that contribute to leukaemogenesis, define new disease subtypes, affect responsiveness to treatment, and might provide novel prognostic markers and therapeutic targets for personalised medicine. Copyright © 2013 Elsevier Ltd. All rights reserved.
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            The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche.

            Bone marrow transplantation is the primary therapy for numerous hematopoietic disorders. The efficiency of bone marrow transplantation depends on the function of long-term hematopoietic stem cells (LT-HSCs), which is markedly influenced by their hypoxic niche. Survival in this low-oxygen microenvironment requires significant metabolic adaptation. Here, we show that LT-HSCs utilize glycolysis instead of mitochondrial oxidative phosphorylation to meet their energy demands. We used flow cytometry to identify a unique low mitochondrial activity/glycolysis-dependent subpopulation that houses the majority of hematopoietic progenitors and LT-HSCs. Finally, we demonstrate that Meis1 and Hif-1alpha are markedly enriched in LT-HSCs and that Meis1 regulates HSC metabolism through transcriptional activation of Hif-1alpha. These findings reveal an important transcriptional network that regulates HSC metabolism. Copyright 2010 Elsevier Inc. All rights reserved.
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              • Record: found
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              Calorie restriction, SIRT1 and metabolism: understanding longevity.

              Calorie restriction (CR) is the only experimental manipulation that is known to extend the lifespan of a number of organisms including yeast, worms, flies, rodents and perhaps non-human primates. In addition, CR has been shown to reduce the incidence of age-related disorders (for example, diabetes, cancer and cardiovascular disorders) in mammals. The mechanisms through which this occurs have been unclear. CR induces metabolic changes, improves insulin sensitivity and alters neuroendocrine function in animals. In this review, we summarize recent findings that are beginning to clarify the mechanisms by which CR results in longevity and robust health, which might open new avenues of therapy for diseases of ageing.
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                Author and article information

                Journal
                9502015
                8791
                Nat Med
                Nat. Med.
                Nature medicine
                1078-8956
                1546-170X
                9 January 2020
                12 December 2016
                January 2017
                13 January 2020
                : 23
                : 1
                : 79-90
                Affiliations
                [1 ]Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
                [2 ]BMU–UTSW Joint Taishan Immunology Group, Binzhou Medical University, Yantai, Shandong, China.
                [3 ]Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
                [4 ]Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
                [5 ]Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
                [6 ]Department of Immunology, Central South University School of Xiangya Medicine, Changsha, Hunan, China.
                [7 ]Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
                [8 ]Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
                [9 ]Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
                Author notes

                AUTHOR 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.

                [10]

                These authors contributed equally to this work.

                Correspondence should be addressed to Z.L. ( zhigang.lu@ 123456utsouthwestern.edu ) or C.C.Z ( Alec.Zhang@ 123456UTSouthwestern.edu ).
                Article
                PMC6956990 PMC6956990 6956990 nihpa1067082
                10.1038/nm.4252
                6956990
                27941793

                Reprints and permissions information is available online at http://www.nature.com/reprints/index.html.

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