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Acidification enhances lactate dehydrogenase– and malate dehydrogenase–mediated promiscuous production of L -2-hydroxyglutarate ( L -2HG) from α-ketoglutarate and stabilizes HIF-1α levels. The metabolite 2-hydroxyglutarate (2HG) can be produced as either a D- R - or L- S - enantiomer, each of which inhibits α-ketoglutarate (αKG)-dependent enzymes involved in diverse biologic processes. Oncogenic mutations in isocitrate dehydrogenase (IDH) produce D -2HG, which causes a pathologic blockade in cell differentiation. On the other hand, oxygen limitation leads to accumulation of L -2HG, which can facilitate physiologic adaptation to hypoxic stress in both normal and malignant cells. Here we demonstrate that purified lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) catalyze stereospecific production of L -2HG via 'promiscuous' reduction of the alternative substrate αKG. Acidic pH enhances production of L -2HG by promoting a protonated form of αKG that binds to a key residue in the substrate-binding pocket of LDHA. Acid-enhanced production of L -2HG leads to stabilization of hypoxia-inducible factor 1 alpha (HIF-1α) in normoxia. These findings offer insights into mechanisms whereby microenvironmental factors influence production of metabolites that alter cell fate and function.

Key Points Lymphomas exhibit heterogeneous genomic alterations, both across and within histological subtypes The molecular heterogeneity underlying lymphoma accounts, at least in part, for variable responses to treatment Lymphoma investigators should incorporate biomarkers into clinical trials to facilitate the clinical development of molecularly targeted therapeutics Techniques for identifying and reporting genomic alterations must be optimized and standardized so that mechanism-based therapies can be effectively applied to the clinical care of lymphoma patients Lymphoma represents a heterogeneous disease both across and within histological subtypes. The future for the treatment of patients with lymphoma will involve matching a targeted therapy to the unique genetic and molecular composition of each lymphoma. This Review discusses biomarkers that can guide treatment decisions for patients with lymphoma, and explore the challenges and strategies for making biomarker-driven personalized medicine a reality in the cure and management of this disease. Modern advances in genomics and cancer biology have produced an unprecedented body of knowledge regarding the molecular pathogenesis of lymphoma. The diverse histological subtypes of lymphoma are molecularly heterogeneous, and most likely arise from distinct oncogenic mechanisms. In parallel to these advances in lymphoma biology, several new classes of molecularly targeted agents have been developed with varying degrees of efficacy across the different types of lymphoma. In general, the development of new drugs for treating lymphoma has been mostly empiric, with a limited knowledge of the molecular target, its involvement in the disease, and the effect of the drug on the target. Thus, the variability observed in clinical responses likely results from underlying molecular heterogeneity. In the era of personalized medicine, the challenge for the treatment of patients with lymphoma will involve correctly matching a molecularly targeted therapy to the unique genetic and molecular composition of each individual lymphoma. In this Review, we discuss current and emerging biomarkers that can guide treatment decisions for patients with lymphoma, and explore the potential challenges and strategies for making biomarker-driven personalized medicine a reality in the cure and management of this disease.

Epigenetic regulation is critical to physiological control of development, cell fate, cell proliferation, genomic integrity and, fundamentally, transcriptional regulation. This epigenetic control occurs at multiple levels including through DNA methylation, histone modification, nucleosome remodelling and modulation of the 3D chromatin structure. Alterations in genes that encode chromatin regulators are common among mesenchymal neoplasms, a collection of more than 160 tumour types including over 60 malignant variants (sarcomas) that have unique and varied genetic, biological and clinical characteristics. Herein, we review those sarcomas in which chromatin pathway alterations drive disease biology. Specifically, we emphasize examples of dysregulation of each level of epigenetic control though mechanisms that include alterations in metabolic enzymes that regulate DNA methylation and histone post-translational modifications, mutations in histone genes, subunit loss or fusions in chromatin remodelling and modifying complexes, and disruption of higher-order chromatin structure. Epigenetic mechanisms of tumorigenesis have been implicated in mesenchymal tumours ranging from chondroblastoma and giant cell tumour of bone to chondrosarcoma, malignant peripheral nerve sheath tumour, synovial sarcoma, epithelioid sarcoma and Ewing sarcoma — all diseases that present in a younger patient population than most cancers. Finally, we review current and potential future approaches for the development of sarcoma therapies based on this emerging understanding of chromatin dysregulation.This Review discusses how the disease biology of many sarcomas is driven by chromatin pathway alterations ranging from dysregulation of DNA methylation, histone modifications and nucleosome remodelling to disruption of higher-order, 3D chromatin structure, with a view to use this knowledge to better develop targeted therapies for patients with sarcoma.

Peripheral T cell lymphoma (PTCL) represents a heterogeneous group of mature T and natural killer cell-derived neoplasms, comprising approximately 10 % of non-Hodgkin lymphoma. Although at least 20 distinct histologic subtypes of PTCL have been identified, the historical treatment approach has been uniform application of anthracycline-based combination chemotherapy, resulting in significantly inferior outcomes compared to B-cell non-Hodgkin lymphoma. Because of the generally poor outcomes with conventional chemotherapy, PTCL represents an unmet medical need, therefore providing the opportunity to evaluate novel agents. Herein, we will review the evolving treatment strategies for PTCL, discuss how different treatment approaches impact the underlying biology of PTCL, and speculate on future targets for therapeutic intervention. We conclude that future efforts to develop effective therapies for PTCL will benefit from a biomarker-driven strategy rather than histologic classification.

In contrast to terminally differentiated cells, cancer cells and stem cells retain the ability to re-enter the cell cycle and proliferate. To proliferate, cells must increase their uptake and catabolism of nutrients to support anabolic cell growth. Intermediates of central metabolic pathways have emerged as key players that influence cell-differentiation ‘decisions’, processes relevant to both oncogenesis and normal development. Consequently, how cells rewire metabolic pathways to support proliferation can have profound consequences for cellular identity. Here, we discuss the metabolic programs that support proliferation, and we explore how metabolic states are intimately entwined with the cell-fate decisions that characterize stem cells and cancer cells. By comparing the metabolism of pluripotent stem cells and cancer cells, we hope to illuminate common metabolic strategies as well as distinct metabolic features that may represent specialized adaptations to unique cellular demands. Like stem cells, cancer cells can rapidly proliferate but, unlike stem cells, they are mostly locked into a malignant identity. Here, Finley and Intlekofer highlight commonalities in anabolic pathways that support proliferation in cancer and stem cells, and point out unique metabolic features that influence self-renewal and differentiation.

Somatic mutations in the isocitrate dehydrogenase 2 gene ( IDH2 ) contribute to the pathogenesis of acute myeloid leukaemia (AML) through the production of the oncometabolite 2-hydroxyglutarate (2HG) 1 – 8 . Enasidenib (AG-221) is an allosteric inhibitor that binds to the IDH2 dimer interface and blocks the production of 2HG by IDH2 mutants 9 , 10 . In a phase I/II clinical trial, enasidenib inhibited the production of 2HG and induced clinical responses in relapsed or refractory IDH2 -mutant AML 11 . Here we describe two patients with IDH2 -mutant AML who had a clinical response to enasidenib followed by clinical resistance, disease progression, and a recurrent increase in circulating levels of 2HG. We show that therapeutic resistance is associated with the emergence of second-site IDH2 mutations in trans , such that the resistance mutations occurred in the IDH2 allele without the neomorphic R140Q mutation. The in trans mutations occurred at glutamine 316 (Q316E) and isoleucine 319 (I319M), which are at the interface where enasidenib binds to the IDH2 dimer. The expression of either of these mutant disease alleles alone did not induce the production of 2HG; however, the expression of the Q316E or I319M mutation together with the R140Q mutation in trans allowed 2HG production that was resistant to inhibition by enasidenib. Biochemical studies predicted that resistance to allosteric IDH inhibitors could also occur via IDH dimer-interface mutations in cis , which was confirmed in a patient with acquired resistance to the IDH1 inhibitor ivosidenib (AG-120). Our observations uncover a mechanism of acquired resistance to a targeted therapy and underscore the importance of 2HG production in the pathogenesis of IDH -mutant malignancies. A new mechanism of acquired clinical resistance in two patients with acute myeloid leukaemia driven by mutant IDH2 is described, in which a second-site mutation on the wild-type allele induces therapeutic resistance to IDH2 inhibitors.

Transcription and pre-mRNA splicing are key steps in the control of gene expression and mutations in genes regulating each of these processes are common in leukaemia 1 , 2 . Despite the frequent overlap of mutations affecting epigenetic regulation and splicing in leukaemia, how these processes influence one another to promote leukaemogenesis is not understood and, to our knowledge, there is no functional evidence that mutations in RNA splicing factors initiate leukaemia. Here, through analyses of transcriptomes from 982 patients with acute myeloid leukaemia, we identified frequent overlap of mutations in IDH2 and SRSF2 that together promote leukaemogenesis through coordinated effects on the epigenome and RNA splicing. Whereas mutations in either IDH2 or SRSF2 imparted distinct splicing changes, co-expression of mutant IDH2 altered the splicing effects of mutant SRSF2 and resulted in more profound splicing changes than either mutation alone. Consistent with this, co-expression of mutant IDH2 and SRSF2 resulted in lethal myelodysplasia with proliferative features in vivo and enhanced self-renewal in a manner not observed with either mutation alone. IDH2 and SRSF2 double-mutant cells exhibited aberrant splicing and reduced expression of INTS3 , a member of the integrator complex 3 , concordant with increased stalling of RNA polymerase II (RNAPII). Aberrant INTS3 splicing contributed to leukaemogenesis in concert with mutant IDH2 and was dependent on mutant SRSF2 binding to cis elements in INTS3 mRNA and increased DNA methylation of INTS3 . These data identify a pathogenic crosstalk between altered epigenetic state and splicing in a subset of leukaemias, provide functional evidence that mutations in splicing factors drive myeloid malignancy development, and identify spliceosomal changes as a mediator of IDH2 -mutant leukaemogenesis. Analyses of transcriptomes from patients with acute myeloid leukaemia identified frequently co-occurring mutations of IDH2 and SRSF2 , which functional analyses showed to have distinct and coordinated leukaemogenic effects on the epigenome and RNA splicing.

Reduced nutrient intake is a widely conserved manifestation of sickness behavior with poorly characterized effects on adaptive immune responses. During infectious challenges, naive T cells encountering their cognate antigen become activated and differentiate into highly proliferative effector T cells. Despite their evident metabolic shift upon activation, it remains unclear how effector T cells respond to changes in nutrient availability in vivo. Here, we show that spontaneous or imposed feeding reduction during infection decreases the numbers of splenic lymphocytes. Effector T cells showed cell-intrinsic responses dependent on the nuclear receptor Farnesoid X Receptor (FXR). Deletion of FXR in T cells prevented starvation-induced loss of lymphocytes and increased effector T cell fitness in nutrient-limiting conditions, but imparted greater weight loss to the host. FXR deficiency increased the contribution of glutamine and fatty acids toward respiration and enhanced cell survival under low-glucose conditions. Provision of glucose during anorexia of infection rescued effector T cells, suggesting that this sugar is a limiting nutrient for activated lymphocytes and that alternative fuel usage may affect cell survival in starved animals. Altogether, we identified a mechanism by which the host scales immune responses according to food intake, featuring FXR as a T cell-intrinsic sensor.

The transcriptional control of T cell exhaustion remains unclear. Wherry and colleagues show that the transcription factor T-bet regulates CD8 + T cell exhaustion and inhibitory receptor expression. T cell exhaustion has a major role in failure to control chronic infection. High expression of inhibitory receptors, including PD-1, and the inability to sustain functional T cell responses contribute to exhaustion. However, the transcriptional control of these processes remains unclear. Here we demonstrate that the transcription factor T-bet regulated the exhaustion of CD8 + T cells and the expression of inhibitory receptors. T-bet directly repressed transcription of the gene encoding PD-1 and resulted in lower expression of other inhibitory receptors. Although a greater abundance of T-bet promoted terminal differentiation after acute infection, high T-bet expression sustained exhausted CD8 + T cells and repressed the expression of inhibitory receptors during chronic viral infection. Persistent antigenic stimulation caused downregulation of T-bet, which resulted in more severe exhaustion of CD8 + T cells. Our observations suggest therapeutic opportunities involving higher T-bet expression during chronic infection.