title: Fasting selectively blocks development of acute lymphoblastic leukemia via leptin-receptor upregulation.
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.
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|BMU-UTSW Joint Taishan Immunology Group, Binzhou Medical University, Yantai, Shandong, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Xie
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Guojin
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Jinhui
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Collins
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Weina
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Xunlei
authors.initials: X
authors.lastname: Kang
authors.affiliation: Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Luo
authors.affiliation: Department of Immunology, Central South University School of Xiangya Medicine, Changsha, Hunan, China.
authors.forename: Yizhou
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Lily Jun-Shen
authors.initials: LJ
authors.lastname: Huang
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Amatruda
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Tamra
authors.initials: T
authors.lastname: Slone
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Naomi
authors.initials: N
authors.lastname: Winick
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Philipp E
authors.identifier: 0000-0003-0680-3392
authors.initials: PE
authors.lastname: Scherer
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|BMU-UTSW Joint Taishan Immunology Group, Binzhou Medical University, Yantai, Shandong, China.
authors.forename: Cheng Cheng
authors.initials: CC
authors.lastname: Zhang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003198:Computer Simulation; D004195:Disease Models, Animal; D005215:Fasting / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D000074462:Positive Regulatory Domain I-Binding Factor 1; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C515448:LEPR protein, human; C513258:Prdm1 protein, mouse; D054411:Receptors, Leptin; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1