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1.
Cell Metab ; 32(6): 981-995.e7, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33264603

RESUMO

Mitochondria constantly adapt to the metabolic needs of a cell. This mitochondrial plasticity is critical to T cells, which modulate metabolism depending on antigen-driven signals and environment. We show here that de novo synthesis of the mitochondrial membrane-specific lipid cardiolipin maintains CD8+ T cell function. T cells deficient for the cardiolipin-synthesizing enzyme PTPMT1 had reduced cardiolipin and responded poorly to antigen because basal cardiolipin levels were required for activation. However, neither de novo cardiolipin synthesis, nor its Tafazzin-dependent remodeling, was needed for T cell activation. In contrast, PTPMT1-dependent cardiolipin synthesis was vital when mitochondrial fitness was required, most notably during memory T cell differentiation or nutrient stress. We also found CD8+ T cell defects in a small cohort of patients with Barth syndrome, where TAFAZZIN is mutated, and in a Tafazzin-deficient mouse model. Thus, the dynamic regulation of a single mitochondrial lipid is crucial for CD8+ T cell immunity.


Assuntos
Aciltransferases/imunologia , Síndrome de Barth/imunologia , Linfócitos T CD8-Positivos/imunologia , Cardiolipinas/imunologia , Mitocôndrias/imunologia , PTEN Fosfo-Hidrolase/imunologia , Animais , Síndrome de Barth/patologia , Linfócitos T CD8-Positivos/citologia , Células Cultivadas , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
2.
Leuk Res ; 39(8): 906-12, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26111797

RESUMO

The MN1 (Meningioma 1) gene is overexpressed in certain subtypes of acute myeloid leukemia (AML) and high levels of MN1 expression in mouse bone marrow cells results in myeloid leukemia. We showed that compared with control bone marrow (BM) MN1 expression was increased (2-fold or more) in 29 out of 73 (40%) pediatric B-cell acute lymphoblastic leukemia (B-ALL) patient BM. Additional analysis of MN1 expression in sub-groups within our cohort carrying different chromosome translocations showed that carriers of the good prognostic marker t(12;21)(TEL-AML1) (n=27) expressed significantly more MN1 than both healthy controls (n=9) (P=0.02) and the group carrying the t(9;22)(BCR-ABL) (n=9) (P=0.001). In addition, AML1 expression was also upregulated in 31 out of 45 (68%) B-ALL patient BM compared with control and there was a significant correlation between MN1 and AML1 expression (r=0.3552, P=0.0167). Retroviral MN1 overexpression increased the colony forming activity of mouse Pro-B/Pre-B cells in vitro. Our results suggest that deregulated MN1 expression contributes to the pathogenesis of pediatric B-ALL. Further investigation into the clinical and biological significance of elevated MN1 expression in TEL-AML1(positive) leukemia might provide insight into additional molecular mechanisms contributing to B-ALL and may lead to improved treatment options for patients.


Assuntos
Linfócitos B/fisiologia , Células da Medula Óssea/fisiologia , Células-Tronco Hematopoéticas/fisiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Proteínas Supressoras de Tumor/genética , Adolescente , Animais , Células da Medula Óssea/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Criança , Pré-Escolar , Ensaio de Unidades Formadoras de Colônias , Feminino , Regulação Leucêmica da Expressão Gênica , Células-Tronco Hematopoéticas/metabolismo , Humanos , Lactente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Cultura Primária de Células , Transativadores , Adulto Jovem
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