Format

Send to

Choose Destination
Nature. 2017 Feb 23;542(7642):479-483. doi: 10.1038/nature21076. Epub 2017 Feb 13.

Metabolic gatekeeper function of B-lymphoid transcription factors.

Author information

1
Department of Systems Biology, Beckman Research Institute and City of Hope National Medical Center, Pasadena, California 91016, USA.
2
City of Hope Comprehensive Cancer Center, Duarte, California 91010, USA.
3
Department of Molecular and Medical Pharmacology, UCLA Metabolomics Center and Crump Institute for Molecular Imaging, University of California Los Angeles, Los Angeles, California 90095, USA.
4
Departments of Laboratory Medicine and Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California 94143, USA.
5
Hämatologie/Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, 07743 Jena, Germany.
6
Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
7
Department of Biochemistry, University of Iowa, Iowa City, Iowa 52242, USA.
8
Centro Ricerca Tettamanti, Clinica Pediatrica, Università di Milano-Bicocca, Ospedale S. Gerardo, 20052 Monza MB, Italy.
9
Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004 Australia.
10
MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
11
Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599.
12
Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California School of Medicine, Los Angeles, California 90095, USA.
13
Department of Internal Medicine and Cancer Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
14
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, Spain.
15
Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany.

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.

PMID:
28192788
PMCID:
PMC5621518
DOI:
10.1038/nature21076
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center