Metabolic gatekeeper function of B-lymphoid transcription factors

Lai N. Chan, Zhengshan Chen, Daniel Braas, Jae Woong Lee, Gang Xiao, Huimin Geng, Kadriye Nehir Cosgun, Christian Hurtz, Seyedmehdi Shojaee, Valeria Cazzaniga, Hilde Schjerven, Thomas Ernst, Andreas Hochhaus, Steven M. Kornblau, Marina Konopleva, Miles A. Pufall, Giovanni Cazzaniga, Grace J. Liu, Thomas A. Milne, H. Phillip KoefflerTheodora S. Ross, Isidro Sánchez-García, Arndt Borkhardt, Keith R. Yamamoto, Ross A. Dickins, Thomas G. Graeber, Markus Müschen

Research output: Contribution to journalArticle

48 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)479-483
Number of pages5
JournalNature
Volume542
Issue number7642
DOIs
StatePublished - Feb 23 2017

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Transcription Factors
Precursor Cell Lymphoblastic Leukemia-Lymphoma
AMP-Activated Protein Kinases
Glucose
Glucocorticoids
Clustered Regularly Interspaced Short Palindromic Repeats
Adenosine Triphosphate
RNA Sequence Analysis
Cannabinoid Receptors
B-Lymphoid Precursor Cells
Citric Acid Cycle
Chromatin Immunoprecipitation
Glucocorticoid Receptors
B-Lymphocytes
Cell Death
Pharmacology
Therapeutics
Genes
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Chan, L. N., Chen, Z., Braas, D., Lee, J. W., Xiao, G., Geng, H., ... Müschen, M. (2017). Metabolic gatekeeper function of B-lymphoid transcription factors. Nature, 542(7642), 479-483. https://doi.org/10.1038/nature21076

Metabolic gatekeeper function of B-lymphoid transcription factors. / Chan, Lai N.; Chen, Zhengshan; Braas, Daniel; Lee, Jae Woong; Xiao, Gang; Geng, Huimin; Cosgun, Kadriye Nehir; Hurtz, Christian; Shojaee, Seyedmehdi; Cazzaniga, Valeria; Schjerven, Hilde; Ernst, Thomas; Hochhaus, Andreas; Kornblau, Steven M.; Konopleva, Marina; Pufall, Miles A.; Cazzaniga, Giovanni; Liu, Grace J.; Milne, Thomas A.; Koeffler, H. Phillip; Ross, Theodora S.; Sánchez-García, Isidro; Borkhardt, Arndt; Yamamoto, Keith R.; Dickins, Ross A.; Graeber, Thomas G.; Müschen, Markus.

In: Nature, Vol. 542, No. 7642, 23.02.2017, p. 479-483.

Research output: Contribution to journalArticle

Chan, LN, Chen, Z, Braas, D, Lee, JW, Xiao, G, Geng, H, Cosgun, KN, Hurtz, C, Shojaee, S, Cazzaniga, V, Schjerven, H, Ernst, T, Hochhaus, A, Kornblau, SM, Konopleva, M, Pufall, MA, Cazzaniga, G, Liu, GJ, Milne, TA, Koeffler, HP, Ross, TS, Sánchez-García, I, Borkhardt, A, Yamamoto, KR, Dickins, RA, Graeber, TG & Müschen, M 2017, 'Metabolic gatekeeper function of B-lymphoid transcription factors', Nature, vol. 542, no. 7642, pp. 479-483. https://doi.org/10.1038/nature21076
Chan LN, Chen Z, Braas D, Lee JW, Xiao G, Geng H et al. Metabolic gatekeeper function of B-lymphoid transcription factors. Nature. 2017 Feb 23;542(7642):479-483. https://doi.org/10.1038/nature21076
Chan, Lai N. ; Chen, Zhengshan ; Braas, Daniel ; Lee, Jae Woong ; Xiao, Gang ; Geng, Huimin ; Cosgun, Kadriye Nehir ; Hurtz, Christian ; Shojaee, Seyedmehdi ; Cazzaniga, Valeria ; Schjerven, Hilde ; Ernst, Thomas ; Hochhaus, Andreas ; Kornblau, Steven M. ; Konopleva, Marina ; Pufall, Miles A. ; Cazzaniga, Giovanni ; Liu, Grace J. ; Milne, Thomas A. ; Koeffler, H. Phillip ; Ross, Theodora S. ; Sánchez-García, Isidro ; Borkhardt, Arndt ; Yamamoto, Keith R. ; Dickins, Ross A. ; Graeber, Thomas G. ; Müschen, Markus. / Metabolic gatekeeper function of B-lymphoid transcription factors. In: Nature. 2017 ; Vol. 542, No. 7642. pp. 479-483.
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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.",
author = "Chan, {Lai N.} and Zhengshan Chen and Daniel Braas and Lee, {Jae Woong} and Gang Xiao and Huimin Geng and Cosgun, {Kadriye Nehir} and Christian Hurtz and Seyedmehdi Shojaee and Valeria Cazzaniga and Hilde Schjerven and Thomas Ernst and Andreas Hochhaus and Kornblau, {Steven M.} and Marina Konopleva and Pufall, {Miles A.} and Giovanni Cazzaniga and Liu, {Grace J.} and Milne, {Thomas A.} and Koeffler, {H. Phillip} and Ross, {Theodora S.} and Isidro S{\'a}nchez-Garc{\'i}a and Arndt Borkhardt and Yamamoto, {Keith R.} and Dickins, {Ross A.} and Graeber, {Thomas G.} and Markus M{\"u}schen",
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AU - Chan, Lai N.

AU - Chen, Zhengshan

AU - Braas, Daniel

AU - Lee, Jae Woong

AU - Xiao, Gang

AU - Geng, Huimin

AU - Cosgun, Kadriye Nehir

AU - Hurtz, Christian

AU - Shojaee, Seyedmehdi

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AU - Hochhaus, Andreas

AU - Kornblau, Steven M.

AU - Konopleva, Marina

AU - Pufall, Miles A.

AU - Cazzaniga, Giovanni

AU - Liu, Grace J.

AU - Milne, Thomas A.

AU - Koeffler, H. Phillip

AU - Ross, Theodora S.

AU - Sánchez-García, Isidro

AU - Borkhardt, Arndt

AU - Yamamoto, Keith R.

AU - Dickins, Ross A.

AU - Graeber, Thomas G.

AU - Müschen, Markus

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N2 - 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.

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