Journal Article

Metabolic gatekeeper function of B-lymphoid transcription factors

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

2017

Overview

The B-lymphoid transcription factors PAX5 and IKZF1 restrict the supply of glucose and energy to B cells to levels that are not enough to fuel a driver-oncogene, thereby acting as tumour suppressors and sensitizing acute lymphoblastic leukaemia B cells to glucocorticoid therapy. Metabolic gatekeeper restricts B-cell malignancies This report examines how in B-cell malignancies, lymphoid transcriptional programs in early differentiation act as metabolic gatekeepers by restricting glucose transport, an important tumour-suppressor function that is subverted during the transformation to cancer. The findings provide a potential explanation for the selective efficacy of glucocorticoid therapy in B-cell malignancies, and suggest potential therapeutic avenues aimed at exploiting their metabolic vulnerabilities. B-lymphoid transcription factors, such as PAX5 and IKZF1, are critical for early B-cell development 1 , 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 AMPK 5 , 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/67 / 631/67/2327 / Adenosine Triphosphate - metabolism / AMP-Activated Protein Kinase Kinases / AMP-Activated Protein Kinases - antagonists & inhibitors / Animals / Apoptosis / ATP / B cells / B-Lymphocytes - drug effects / B-Lymphocytes - metabolism / Carcinogenesis - genetics / Carrier Proteins - agonists / Carrier Proteins - metabolism / Cell Death / Chromatin Immunoprecipitation / Citric Acid Cycle / Cloning / Disease Models, Animal / Energy / Energy Metabolism - genetics / Female / Gene expression / Gene Expression Regulation, Neoplastic / Glucocorticoids - pharmacology / Glucocorticoids - therapeutic use / Glucose / Glucose - metabolism / Humanities and Social Sciences / Humans / Ikaros Transcription Factor - metabolism / Kinases / Lesions / letter / Leukemia / Metabolism / Metabolites / Mice / Mice, Transgenic / multidisciplinary / PAX5 Transcription Factor - deficiency / PAX5 Transcription Factor - genetics / PAX5 Transcription Factor - metabolism / Physiological aspects / Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy / Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics / Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - metabolism / Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - pathology / Protein Serine-Threonine Kinases - metabolism / Proteins / Pyruvic Acid - metabolism / Receptor, Cannabinoid, CB2 - agonists / Receptor, Cannabinoid, CB2 - metabolism / Receptors, Glucocorticoid - metabolism / Rodents / Science / Sequence Analysis, RNA / Transcription factors / Transcription Factors - metabolism