Journal article
Metabolic gatekeeper function of B-lymphoid transcription factors
Nature (London), Vol.542(7642), pp.479-483
02/23/2017
DOI: 10.1038/nature21076
PMCID: PMC5621518
PMID: 28192788
Abstract
B-lymphoid transcription factors, such as PAX5 and IKZF1, are critical for early B-cell development, yet lesions of the genes encoding these transcription factors occur in over 80% of cases of pre-B-cell acute lymphoblastic leukaemia (ALL). The importance of these lesions in ALL has, until now, remained unclear. Here, by combining studies using chromatin immunoprecipitation with sequencing and RNA sequencing, we identify a novel B-lymphoid program for transcriptional repression of glucose and energy supply. Our metabolic analyses revealed that PAX5 and IKZF1 enforce a state of chronic energy deprivation, resulting in constitutive activation of the energy-stress sensor AMPK. Dominant-negative mutants of PAX5 and IKZF1, however, relieved this glucose and energy restriction. In a transgenic pre-B ALL mouse model, the heterozygous deletion of Pax5 increased glucose uptake and ATP levels by more than 25-fold. Reconstitution of PAX5 and IKZF1 in samples from patients with pre-B ALL restored a non-permissive state and induced energy crisis and cell death. A CRISPR/Cas9-based screen of PAX5 and IKZF1 transcriptional targets identified the products of NR3C1 (encoding the glucocorticoid receptor), TXNIP (encoding a glucose-feedback sensor) and CNR2 (encoding a cannabinoid receptor) as central effectors of B-lymphoid restriction of glucose and energy supply. Notably, transport-independent lipophilic methyl-conjugates of pyruvate and tricarboxylic acid cycle metabolites bypassed the gatekeeper function of PAX5 and IKZF1 and readily enabled leukaemic transformation. Conversely, pharmacological TXNIP and CNR2 agonists and a small-molecule AMPK inhibitor strongly synergized with glucocorticoids, identifying TXNIP, CNR2 and AMPK as potential therapeutic targets. Furthermore, our results provide a mechanistic explanation for the empirical finding that glucocorticoids are effective in the treatment of B-lymphoid but not myeloid malignancies. Thus, B-lymphoid transcription factors function as metabolic gatekeepers by limiting the amount of cellular ATP to levels that are insufficient for malignant transformation.
Details
- Title: Subtitle
- Metabolic gatekeeper function of B-lymphoid transcription factors
- Creators
- Lai N Chan - City of Hope Comprehensive Cancer Center, Duarte, California 91010, USAZhengshan Chen - City of Hope Comprehensive Cancer Center, Duarte, California 91010, USADaniel Braas - Department of Molecular and Medical Pharmacology, UCLA Metabolomics Center and Crump Institute for Molecular Imaging, University of California Los Angeles, Los Angeles, California 90095, USAJae-Woong Lee - City of Hope Comprehensive Cancer Center, Duarte, California 91010, USAGang Xiao - City of Hope Comprehensive Cancer Center, Duarte, California 91010, USAHuimin Geng - Departments of Laboratory Medicine and Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California 94143, USAKadriye Nehir Cosgun - City of Hope Comprehensive Cancer Center, Duarte, California 91010, USAChristian Hurtz - Departments of Laboratory Medicine and Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California 94143, USASeyedmehdi Shojaee - Departments of Laboratory Medicine and Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California 94143, USAValeria Cazzaniga - Departments of Laboratory Medicine and Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California 94143, USAHilde Schjerven - Departments of Laboratory Medicine and Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California 94143, USAThomas Ernst - Hämatologie/Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, 07743 Jena, GermanyAndreas Hochhaus - Hämatologie/Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, 07743 Jena, GermanySteven M Kornblau - Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USAMarina Konopleva - Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USAMiles A Pufall - Department of Biochemistry, University of Iowa, Iowa City, Iowa 52242, USAGiovanni Cazzaniga - Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Ospedale S. Gerardo, 20052 Monza MB, ItalyGrace J Liu - Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004 AustraliaThomas A Milne - MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UKH Phillip Koeffler - Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California School of Medicine, Los Angeles, California 90095, USATheodora S Ross - Department of Internal Medicine and Cancer Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USAIsidro Sánchez-García - Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca and Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, SpainArndt Borkhardt - Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, GermanyKeith R Yamamoto - Departments of Laboratory Medicine and Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California 94143, USARoss A Dickins - Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004 AustraliaThomas G Graeber - Department of Molecular and Medical Pharmacology, UCLA Metabolomics Center and Crump Institute for Molecular Imaging, University of California Los Angeles, Los Angeles, California 90095, USAMarkus Müschen - City of Hope Comprehensive Cancer Center, Duarte, California 91010, USA
- Resource Type
- Journal article
- Publication Details
- Nature (London), Vol.542(7642), pp.479-483
- DOI
- 10.1038/nature21076
- PMID
- 28192788
- PMCID
- PMC5621518
- NLM abbreviation
- Nature
- ISSN
- 0028-0836
- eISSN
- 1476-4687
- Publisher
- England
- Grant note
- R00 CA149088 / NCI NIH HHS R01 CA139032 / NCI NIH HHS Wellcome Trust R01 CA172558 / NCI NIH HHS 55108547 / Howard Hughes Medical Institute P30 DK063720 / NIDDK NIH HHS MC_UU_12009/6 / Medical Research Council R01 CA157644 / NCI NIH HHS P30 CA086862 / NCI NIH HHS R35 CA197628 / NCI NIH HHS R01 CA213138 / NCI NIH HHS MC_UU_00016/6 / Medical Research Council R01 CA137060 / NCI NIH HHS Wellcome Trust Senior Investigator Award R01 CA169458 / NCI NIH HHS
- Language
- English
- Date published
- 02/23/2017
- Academic Unit
- Biochemistry and Molecular Biology
- Record Identifier
- 9984024531402771
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