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1.
Cell ; 175(1): 101-116.e25, 2018 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-30220459

RESUMO

IDH1 mutations are common in low-grade gliomas and secondary glioblastomas and cause overproduction of (R)-2HG. (R)-2HG modulates the activity of many enzymes, including some that are linked to transformation and some that are probably bystanders. Although prior work on (R)-2HG targets focused on 2OG-dependent dioxygenases, we found that (R)-2HG potently inhibits the 2OG-dependent transaminases BCAT1 and BCAT2, likely as a bystander effect, thereby decreasing glutamate levels and increasing dependence on glutaminase for the biosynthesis of glutamate and one of its products, glutathione. Inhibiting glutaminase specifically sensitized IDH mutant glioma cells to oxidative stress in vitro and to radiation in vitro and in vivo. These findings highlight the complementary roles for BCATs and glutaminase in glutamate biosynthesis, explain the sensitivity of IDH mutant cells to glutaminase inhibitors, and suggest a strategy for maximizing the effectiveness of such inhibitors against IDH mutant gliomas.


Assuntos
Glioma/metabolismo , Ácido Glutâmico/biossíntese , Transaminases/fisiologia , Linhagem Celular Tumoral , Glioma/fisiopatologia , Ácido Glutâmico/efeitos dos fármacos , Glutaratos/metabolismo , Glutaratos/farmacologia , Homeostase/efeitos dos fármacos , Humanos , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/fisiologia , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/fisiologia , Mutação , Oxirredução/efeitos dos fármacos , Proteínas da Gravidez/genética , Proteínas da Gravidez/fisiologia , Transaminases/antagonistas & inibidores , Transaminases/genética
2.
Proc Natl Acad Sci U S A ; 115(16): E3741-E3748, 2018 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-29610306

RESUMO

Inactivation of the retinoblastoma gene (RB1) product, pRB, is common in many human cancers. Targeting downstream effectors of pRB that are central to tumorigenesis is a promising strategy to block the growth of tumors harboring loss-of-function RB1 mutations. One such effector is retinoblastoma-binding protein 2 (RBP2, also called JARID1A or KDM5A), which encodes an H3K4 demethylase. Binding of pRB to RBP2 has been linked to the ability of pRB to promote senescence and differentiation. Importantly, genetic ablation of RBP2 is sufficient to phenocopy pRB's ability to induce these cellular changes in cell culture experiments. Moreover, germline Rbp2 deletion significantly impedes tumorigenesis in Rb1+/- mice. The value of RBP2 as a therapeutic target in cancer, however, hinges on whether loss of RBP2 could block the growth of established tumors as opposed to simply delaying their onset. Here we show that conditional, systemic ablation of RBP2 in tumor-bearing Rb1+/- mice is sufficient to slow tumor growth and significantly extend survival without causing obvious toxicity to the host. These findings show that established Rb1-null tumors require RBP2 for growth and further credential RBP2 as a therapeutic target in human cancers driven by RB1 inactivation.


Assuntos
Proteínas de Ligação a DNA/fisiologia , Código das Histonas/fisiologia , Histona Desmetilases com o Domínio Jumonji/fisiologia , Terapia de Alvo Molecular/métodos , Proteínas de Neoplasias/fisiologia , Neoplasias Hipofisárias/enzimologia , Proteína do Retinoblastoma/deficiência , Neoplasias da Glândula Tireoide/enzimologia , Alelos , Animais , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Ecocardiografia , Ativação Enzimática/efeitos dos fármacos , Fibroblastos , Genes do Retinoblastoma , Defeitos dos Septos Cardíacos/genética , Código das Histonas/efeitos dos fármacos , Integrases/efeitos dos fármacos , Histona Desmetilases com o Domínio Jumonji/deficiência , Histona Desmetilases com o Domínio Jumonji/genética , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/terapia , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/genética , Tamoxifeno/farmacologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/terapia , Transgenes/efeitos dos fármacos
3.
Sci Immunol ; 7(69): eabn8041, 2022 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-35333545

RESUMO

Targeting the potent immunosuppressive properties of FOXP3+ regulatory T cells (Tregs) has substantial therapeutic potential for treating autoimmune and inflammatory diseases. Yet, the molecular mechanisms controlling Treg homeostasis, particularly during inflammation, remain unclear. We report that caspase-8 is a central regulator of Treg homeostasis in a context-specific manner that is decisive during immune responses. In mouse genetic models, targeting caspase-8 in Tregs led to accumulation of effector Tregs resistant to apoptotic cell death. Conversely, inflammation induced the MLKL-dependent necroptosis of caspase-8-deficient lymphoid and tissue Tregs, which enhanced immunity to a variety of chronic infections to promote clearance of viral or parasitic pathogens. However, improved immunity came at the risk of lethal inflammation in overwhelming infections. Caspase-8 inhibition using a clinical-stage compound revealed that human Tregs have heightened sensitivity to necroptosis compared with conventional T cells. These findings reveal a fundamental mechanism in Tregs that could be targeted to manipulate the balance between immune tolerance versus response for therapeutic benefit.


Assuntos
Caspase 8/metabolismo , Tolerância Imunológica , Linfócitos T Reguladores , Animais , Homeostase , Inflamação/metabolismo , Camundongos
4.
Cell Death Differ ; 27(12): 3374-3385, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32612106

RESUMO

FOXP3+ regulatory T (Treg) cells are essential for maintaining immunological tolerance. Given their importance in immune-related diseases, cancer and obesity, there is increasing interest in targeting the Treg cell compartment therapeutically. New pharmacological inhibitors that specifically target the prosurvival protein MCL-1 may provide this opportunity, as Treg cells are particularly reliant upon this protein. However, there are two distinct isoforms of MCL-1; one located at the outer mitochondrial membrane (OMM) that is required to antagonize apoptosis, and another at the inner mitochondrial membrane (IMM) that is reported to maintain IMM structure and metabolism via ATP production during oxidative phosphorylation. We set out to elucidate the relative importance of these distinct biological functions of MCL-1 in Treg cells to assess whether MCL-1 inhibition might impact upon the metabolism of cells able to resist apoptosis. Conditional deletion of Mcl1 in FOXP3+ Treg cells resulted in a lethal multiorgan autoimmunity due to the depletion of the Treg cell compartment. This striking phenotype was completely rescued by concomitant deletion of the apoptotic effector proteins BAK and BAX, indicating that apoptosis plays a pivotal role in the homeostasis of Treg cells. Notably, MCL-1-deficient Treg cells rescued from apoptosis displayed normal metabolic capacity. Moreover, pharmacological inhibition of MCL-1 in Treg cells resistant to apoptosis did not perturb their metabolic function. We conclude that Treg cells require MCL-1 only to antagonize apoptosis and not for metabolism. Therefore, MCL-1 inhibition could be used to manipulate Treg cell survival for clinical benefit without affecting the metabolic fitness of cells resisting apoptosis.


Assuntos
Apoptose/imunologia , Fatores de Transcrição Forkhead/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Animais , Apoptose/genética , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Feminino , Fatores de Transcrição Forkhead/genética , Deleção de Genes , Homeostase/imunologia , Tolerância Imunológica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Transdução de Sinais
5.
Cancer Res ; 76(9): 2766-2777, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26960974

RESUMO

Activating mutations in tyrosine kinases (TKs) drive pediatric high-risk acute lymphoblastic leukemia (ALL) and confer resistance to standard chemotherapy. Therefore, there is urgent need to characterize dysregulated TK signaling axes in patients with ALL and identify actionable kinase targets for the development of therapeutic strategies. Here, we present the first study to quantitatively profile TK activity in xenografted patient biopsies of high-risk pediatric ALL. We integrated a quantitative phosphotyrosine profiling method with 'spike-in' stable isotope labeling with amino acids in cell culture (SILAC) and quantified 1394 class I phosphorylation sites in 16 ALL xenografts. Moreover, hierarchical clustering of phosphotyrosine sites could accurately classify these leukemias into either B or T-cell lineages with the high-risk early T-cell precursor (ETP) and Ph-like ALL clustering as a distinct group. Furthermore, we validated this approach by using specific kinase pathway inhibitors to perturb ABL1, FLT3, and JAK TK signaling in four xenografted patient samples. By quantitatively assessing the tyrosine phosphorylation status of activated kinases in xenograft models of ALL, we were able to identify and validate clinically relevant targets. Therefore, this study highlights the application and potential of phosphotyrosine profiling for identifying clinically relevant kinase targets in leukemia.

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