Metabolic gatekeeper function of B-lymphoid transcription factors

Abstract

B-lymphoid transcription factors, such as PAX5 and IKZF1, are critical for early B-cell development1,2, yet lesions of the genes encoding these transcription factors occur in over 80% of cases of pre-B-cell acute lymphoblastic leukaemia (ALL)3,4. 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 AMPK5,6,7. 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)8, TXNIP (encoding a glucose-feedback sensor)9 and CNR2 (encoding a cannabinoid receptor)10 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.

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Figure 1: A B-lymphoid transcriptional program to regulate factors of glucose uptake and utilization.
Figure 2: LKB1–AMPK is required to balance glucose and energy metabolism in pre-B ALL.
Figure 3: Mechanistic contribution of PAX5 targets to regulation of glucose and energy metabolism in pre-B ALL.
Figure 4: Transcriptional restriction of glucose and energy supply prevents oncogenic signalling and pre-B cell transformation.

Change history

  • 30 May 2018

    In the NR3C1 plot of Fig. 3c (left) of this Letter, the curves for TXNIP (middle) were inadvertently plotted. This has been corrected online, and see Supplementary Information to the Amendment for the original Fig. 3c.

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Acknowledgements

This work was supported by the NIH/NCI through Outstanding Investigator Award R35CA197628 (to M.M.), R01CA137060, R01CA157644 and R01CA172558 (to M.M.), a Wellcome Trust Senior Investigator Award and a Leukemia and Lymphoma Scholar award (to M.M.), the Howard Hughes Medical Institute HHMI-55108547 (to M.M.), the Alex’s Lemonade Stand Foundation for Childhood Cancer (to M.M.), the William Lawrence & Blanche Hughes Foundation for childhood cancer (to M.M.), the Norman and Sadie Lee Foundation (for Pediatric Cancer, to M.M.), the Falk Trust through a Falk Medical Research Trust Catalyst Award (to M.M.), Cancer Research Institute (CRI) through a Clinic and Laboratory Integration Program (CLIP) grant (to M.M.), the Melanoma Research Alliance Established Investigator Award (to T.G.G.), the German Bundesministerium für Bildung und Forschung, BMBF (to A.H.) and the German Carreras Foundation (DJCLS R13/26) (to A.B. and I.S.-G.). T.G.G. is an American Cancer Society Research Scholar. M.M. is a Howard Hughes Medical Institute (HHMI) Faculty Scholar.

Author information

M.M. conceived the study. L.N.C. and M.M. wrote the paper and designed experiments. L.N.C., Z.C., D.B., J.-W.L., G.X., K.N.C., C.H., S.S. and V.C. performed experiments and analysed data. S.M.K. performed functional proteomics. H.G. performed biostatistical analyses. T.A.M., T.E., A.H., M.K. and G.C. provided and characterized patient samples. I.S.-G., A.B., T.S.R., G.J.L. and R.A.D. provided mouse models. M.A.P., K.R.Y., G.J.L., R.A.D., I.S.-G., A.B., H.P.K. and H.S. provided specific expertise in NR3C1, PAX5 and IKZF1 function. D.B. and T.G.G. performed experimentation and provided analysis and expertise in metabolomics.

Correspondence to Markus Müschen.

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Competing interests

The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Frequent genetic lesions of B-lymphoid transcription factors in B-cell lineage leukaemia.

a, Gene expression of B-lymphoid transcription factors (top) as well as positive (middle) and negative (bottom) regulators of glucose uptake and energy supply upon inducible restoration of Pax5 (GEO accession number: GSE52870)38 in haploinsufficient pre-B leukaemia cells. b, Lesions in PAX5, IKZF1, EBF1 and TCF3 were studied in clinical trials for B-lymphoid ALL in children (P9906; n = 187; top) and adults (MDACC; n = 92; bottom). Red and grey boxes denote patient samples with detected lesions. c, Protein expression of PAX5 and IKZF1 was examined by western blot in ten patient-derived pre-B ALL samples. The control samples were CD19+ B cells from four healthy donors. d, ChIP–seq analysis for binding of B-lymphoid transcription factors in human B cells (ENCODE cell ID: GM12878) to promoter regions of molecules implicated in positive (INSR, GLUT1, GLUT3, GLUT6, HK2, G6PD, LKB1) and negative (NR3C1, TXNIP, CNR2) regulation of glucose uptake and utilization. e, Recruitment of PAX5 was confirmed by quantitative ChIP in patient-derived pre-B ALL cells. Data shown as mean ± s.d. from three independent experiments and assessed by two-tailed t-test. For gel source data, see Supplementary Fig. 1. Source data

Extended Data Figure 2 The B-lymphoid transcription factor PAX5 functions as a metabolic gatekeeper.

a, Protein levels of PAX5 and IKZF1 in haploinsufficient patient-derived pre-B ALL cells and pre-B ALL cells expressing functional PAX5 and IKZF1. b, Number of viable cells and cell viability upon inducible activation of PAX5 in haploinsufficient patient-derived pre-B ALL (PAX5) cells. c, To test whether Pax5 functions as metabolic gatekeeper, BCR–ABL1-induced changes in glycolytic activity and capacity (ECAR), glucose uptake, and ATP levels (normalized to cell numbers) were studied in Pax5 wild-type and Pax5 haploinsufficient pre-B cells in the presence or absence of a BCR–ABL1-transgene. Data shown as mean ± s.d. from three independent experiments and assessed by two-tailed t-test (b, left; c) or two-way ANOVA (b, right). For gel source data, see Supplementary Fig. 1. Source data

Extended Data Figure 3 Divergent metabolic characteristics of myeloid and B-lineage leukaemia.

a, Glycolytic reserve (ECAR) and mitochondrial functions (OCR) in patient-derived myeloid (CML) and B-lymphoid (Ph+ ALL) leukaemia samples (n = 5, each in triplicate). Values were normalized to total protein and are shown as mean ± s.d., assessed by two-tailed t-test. b, Mouse pre-B ALL cells were reprogrammed into myeloid differentiation using a doxycycline-inducible TetOn-Cebpa vector system, and characterized by flow cytometry (representative results from three independent experiments). c, Heat map of gene expression of glucose uptake and metabolism regulators (GEO accession number: GSE32330)12. d, Western blots of mouse pre-B ALL cells upon B-to-myeloid cell reprogramming to verify gene expression changes. For gel source data, see Supplementary Fig. 1. Source data

Extended Data Figure 4 The energy stress sensor LKB1–AMPK plays a pro-survival role and modulates glucose uptake and energy supply in pre-B ALL.

a, Lkb1fl/fl mice were crossed with Cre-deleter strains for deletion at early pre-B-cell stages (Mb1) and in fully mature B cells (Cd21). B-cell populations in bone marrow and spleen (n = 3 litter mates) were characterized by flow cytometry analysis. b, The catalytic subunit of Ampk has two isoforms, α1 and α2. Analysis of published gene expression data (GSE38463)38 revealed that expression of the α1-form peaks at later stages of B-cell development, whereas expression of both Lkb1 and the α2-form of Ampk peaks in pre-B cells. For this reason, we studied the consequences of inducible ablation of Lkb1 and Ampka2 in mouse models of BCR–ABL1-transformed pre-B ALL cells. Protein levels of Lkb1 and Ampkα2 were verified by western blots. c, Viable cell counts upon Cre-mediated deletion of Lkb1 or Ampka2 or on treatment with an empty vector (EV). d, Apoptosis following Lkb1 deletion was monitored by annexin V/ 7-aminoactinomycin D (7AAD) staining. e, Colony-forming ability was assessed by serial re-plating upon deletion of Lkb1 in pre-B ALL cells. f, Glucose uptake and ATP levels (normalized to cell numbers) were measured following Cre-mediated deletion of Ampka2. g, Luciferase bioimaging of transplant recipient mice injected with Lkb1fl/fl pre-B ALL cells transduced with 4-OHT-inducible Cre or an empty vector and treated with tamoxifen (0.4 mg per mouse; n = 7 per group). h, Overall survival was assessed by a Kaplan–Meier analysis (P value calculated by Mantel–Cox log-rank test). i, Leukaemia samples developed in recipient mice (Fig. 2d) were genotyped for the presence of either floxed or deleted Lkb1 and Ampka2 alleles (n = 3 mice). Representative FACS plots and images from three independent experiments are shown (a, d, e). Data shown as mean ± s.d. from three independent experiments and assessed by two-way ANOVA (c) or two-tailed t-test (e, f). For gel source data, see Supplementary Fig. 1. Source data

Extended Data Figure 5 LKB1 and AMPK are independent predictors of poor clinical outcome for patients with pre-B ALL.

a, b, Children with high-risk pre-B ALL (P9906, n = 207) were divided into two groups based on higher- or lower-than-median mRNA levels of LKB1 (a) or AMPKΑ2 (b). c, d, Adults with acute myeloid leukaemia (AML; The Cancer Genome Atlas, n = 184) were divided into two groups based on higher- or lower-than-median mRNA levels of LKB1 (c) or AMPKΑ2 (d). Overall survival of patients was assessed in the two groups by Kaplan–Meier analysis. A log-rank test was used to assess statistical significance (ad). e, Frequencies of somatic mutations in the coding regions of EBF1 (top, blue), IKZF1 (middle, grey) and PAX5 (bottom, red) from the Catalogue of Somatic Mutations in Cancer (COSMIC) database are plotted for pre-B ALL and various subtypes of mature B-cell lymphoma. Somatic mutations in the 5′ UTR regions of EBF1, IKZF1 and PAX5 frequently represent by-products of somatic hypermutation during normal B-cell development and are not included in this analysis. PCNL, primary central nervous system lymphoma.

Extended Data Figure 6 Divergent functions of Lkb1 in BCR–ABL1-driven pre-B ALL and myeloid leukaemia.

a, Staining of Lkb1fl/fl BCR–ABL1 myeloid (CML-like) and B-lineage (Ph+ ALL-like) leukaemia cells with (Cre) or without (empty vector (EV)) deletion of Lkb1 for the surface markers CD19, B220 (B-lymphoid), Sca-1 and CD13 (myeloid). b, Phosphorylation of AMPKα-T172, AKT-S473 and S6-S235 and protein levels of cell-cycle checkpoint molecules Arf, p53 and p27 following Lkb1-deletion. c, Viable cell counts upon deletion of Lkb1. d, Glucose uptake and ATP levels (normalized to cell numbers) in myeloid and B-lymphoid leukaemia cells upon Lkb1-deletion (n = 6). Data are shown as mean ± s.d. e, Cell-cycle analyses were performed by measuring BrdU incorporation in combination with 7AAD staining. Percentages of cells in G0/1, S, and G2/M phases are shown. Viability following Lkb1 deletion was monitored by annexin V/7AAD staining. Representative FACS plots from three independent experiments are shown (a, e). Data shown as mean ± s.d. from three independent experiments (c, e), assessed by two-tailed t-test (ce). For gel source data, see Supplementary Fig. 1. Source data

Extended Data Figure 7 Activity of the energy-stress sensor LKB1 represents a specific vulnerability of B-lymphoid leukaemia.

a, b, Glycolytic profiles (ECAR; a) and mitochondrial functions (OCR; b) upon Lkb1-deletion in B-lymphoid leukaemia cells with (left) or without (right) B-to-myeloid cell reprogramming. Values were normalized to total protein (n = 6). c, AMP levels in sorted B-lymphoid and B-to-myeloid reprogrammed cells are shown as log2-transformed relative amounts (the amount in Lkb1-deleted cells divided by the average amount in control samples), and data were baseline-centred (the baseline is equal to the average amount in control samples; n = 3). d, Phosphorylation of Ampkα-T172, Ulk-S555, Raptor-S792 and Acc-S79 was assessed by western blots. Data shown as mean ± s.d. and assessed by two-tailed t-test (ac). For gel source data, see Supplementary Fig. 1. Source data

Extended Data Figure 8 Small molecule inhibition of AMPK in human pre-B ALL.

a, Human leukaemia and lymphoma cells (n = 4 biological replicates for B-cell lymphoma and pre-B ALL; n = 3 biological replicates for CML; each in triplicate) were treated with BML275 (72 h), and relative viability was assessed. b, Apoptosis was examined by annexin V/7AAD staining in patient-derived pre-B ALL samples (n = 3) upon treatment with BML275 (10 μmol/l). c, Phospho-ACC-S79 in patient-derived pre-B ALL samples (n = 5) following overnight treatment with control (−) or BML275 (+, 10 μmol/l) was assessed. d, Phosphorylation of S6-S235/236 and Akt-S473 in patient-derived pre-B ALL samples (n = 6) following overnight treatment with control (−) or BML275 (+, 10 μmol/l) was assessed. e, Levels of AMP (normalized to cell numbers) in patient-derived CML (CML5 and CML6) and Ph+ ALL (ICN1 and PDX2) cells following treatment with control or BML275 (10 μmol/l for 12 h). Plotted are log2-transformed average relative amounts (amount in cells treated with BML275 divided by the average amount of that in control cells; two cases per group; each in triplicate); data were median-centred. Median-centring was performed separately for CML5, CML6, ICN1 and PDX2 samples. f, Patient-derived CML (left) and pre-B ALL (middle) cells as well as MYC-driven B-cell lymphoma cell lines (right) were treated with BML275 (10 μmol/l) or vehicle control for 6 h. Glycolytic profiles (ECAR) and mitochondrial functions (OCR) were measured (normalized to total protein; n = 6; f). Data shown as mean ± s.d. and assessed by two-tailed t-test (e, f). Source data

Extended Data Figure 9 Mechanistic contribution of PAX5 targets.

a, b, Representative FACS plots from CRISPR-based gene editing experiments (a). CRISPR complexes were delivered to patient-derived PAX5-haploinsufficient pre-B ALL cells along with RFP-tagged gRNAs to direct dCas9 (CRISPR-mediated gene activation) or Cas9 (CRISPR-mediated gene deletion) to specific PAX5 target genes (for example, NR3C1; left). Upon inducible activation of GFP-tagged PAX5 or an empty vector (EV) in patient-derived pre-B ALL cells, enrichment or depletion of GFP+ cells carrying RFP-tagged gRNAs (RFP+) was monitored by flow cytometry (right; NT, non-targeting; g-53, gRNA clone 53 for deletion of NR3C1). Changes in percentage of GFP+ cells carrying the indicated gRNAs following induction, as compared to cells carrying the non-targeting gRNA (b). c, d, In mouse pre-B ALL models for genetic loss of Nr3c1, Cnr2, and Txnip function, responses to prednisolone (Pred) were measured (c) and protein levels of Nr3c1, Txnip and Cnr2 were examined (d). e, In a patient-derived PAX5-haploinsufficient pre-B ALL sample (PAX5Δ; left), dexamethasone responses upon inducible activation of PAX5 or empty vector were measured. In a patient-derived PAX5 wild-type pre-B ALL sample (PAX5WT; right), effects of DN-PAX5 on dexamethasone responses were measured. Likewise, dose–response curves for dexamethasone were measured in two patient-derived pre-B ALL samples carrying either wild-type or deleted IKZF1 upon induction of DN-IKZF1 or IKZF1 expression, respectively. Data shown as mean ± s.d. from three independent experiments and assessed by two-tailed t-test (b) or two-way ANOVA (c, e). Source data

Extended Data Figure 10 Targeting AMPK, CNR2 and TXNIP in combination with glucocorticoids.

a, Three different patient-derived pre-B ALL samples were treated with the AMPK inhibitor BML275, prednisolone or a combination of the two for 72 h. b, Three different patient-derived pre-B ALL samples were treated with the CNR2 agonist HU308, prednisolone (Pred), or a combination of the two for 72 h. c, d, Three different patient-derived pre-B ALL samples were treated with the TXNIP agonist 3-OMG (c) or d-allose (d), prednisolone, or a combination of the two for 72 h. Relative viability was assessed (a–d). Combination index (CI) values at ED50 are shown. Prednisolone concentrations used were twofold higher than those of BML275. All data shown as mean ± s.d. (n = 3 independent experiments). Source data

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Chan, L., Chen, Z., Braas, D. et al. Metabolic gatekeeper function of B-lymphoid transcription factors. Nature 542, 479–483 (2017). https://doi.org/10.1038/nature21076

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