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

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

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.

Related collections

Most cited references 37

Record: found
Abstract: found
Article: not found

The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche.

Tugba Simsek, Fatih Kocabas, Junke Zheng … (2010)

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.

0 comments Cited 332 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Acute lymphoblastic leukaemia.

Hiroto Inaba, Mel F Greaves, Charles Mullighan (2013)

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.

0 comments Cited 317 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma.

Andrew P. Weng, John M Millholland, Yumi Yashiro-Ohtani … (2006)

Human acute T-cell lymphoblastic leukemias and lymphomas (T-ALL) are commonly associated with gain-of-function mutations in Notch1 that contribute to T-ALL induction and maintenance. Starting from an expression-profiling screen, we identified c-myc as a direct target of Notch1 in Notch-dependent T-ALL cell lines, in which Notch accounts for the majority of c-myc expression. In functional assays, inhibitors of c-myc interfere with the progrowth effects of activated Notch1, and enforced expression of c-myc rescues multiple Notch1-dependent T-ALL cell lines from Notch withdrawal. The existence of a Notch1-c-myc signaling axis was bolstered further by experiments using c-myc-dependent murine T-ALL cells, which are rescued from withdrawal of c-myc by retroviral transduction of activated Notch1. This Notch1-mediated rescue is associated with the up-regulation of endogenous murine c-myc and its downstream transcriptional targets, and the acquisition of sensitivity to Notch pathway inhibitors. Additionally, we show that primary murine thymocytes at the DN3 stage of development depend on ligand-induced Notch signaling to maintain c-myc expression. Together, these data implicate c-myc as a developmentally regulated direct downstream target of Notch1 that contributes to the growth of T-ALL cells.

0 comments Cited 239 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-journal-id): 9502015

Journal ID (pubmed-jr-id): 8791

Journal ID (nlm-ta): Nat Med

Journal ID (iso-abbrev): Nat. Med.

Title: Nature medicine

ISSN (Print): 1078-8956

ISSN (Electronic): 1546-170X

Publication date Nihms-submitted: 9 January 2020

Publication date (Electronic): 12 December 2016

Publication date (Print): January 2017

Publication date PMC-release: 13 January 2020

Volume: 23

Issue: 1

Pages: 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

Accession ID: PMC6956990 Pmcid ID: PMC6956990 Pmc-uid ID: 6956990 Manuscript ID: nihpa1067082

DOI: 10.1038/nm.4252

PMC ID: 6956990

PubMed ID: 27941793

SO-VID: ec6446a5-fc7a-451b-ad00-de127e305884

License:

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

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

Read this article at

Abstract

Related collections

Malaria vaccine development

Most cited references 37

The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche.

Acute lymphoblastic leukaemia.

c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma.

Author and article information

Journal

Affiliations

Author notes

Article

History

Categories

Comments

Comment on this article

Similar content 118

Cited by 56

Most referenced authors 1,171