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1.
Blood Adv ; 5(3): 700-710, 2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33560378

RESUMO

T-cell acute lymphoblastic leukemia (T-ALL) represents the malignant expansion of immature T cells blocked in their differentiation. T-ALL is still associated with a poor prognosis, mainly related to occurrence of relapse or refractory disease. A critical medical need therefore exists for new therapies to improve the disease prognosis. Adenylate kinase 2 (AK2) is a mitochondrial kinase involved in adenine nucleotide homeostasis recently reported as essential in normal T-cell development, as defective AK2 signaling pathway results in a severe combined immunodeficiency with a complete absence of T-cell differentiation. In this study, we show that AK2 is constitutively expressed in T-ALL to varying levels, irrespective of the stage of maturation arrest or the underlying oncogenetic features. T-ALL cell lines and patient T-ALL-derived xenografts present addiction to AK2, whereas B-cell precursor ALL cells do not. Indeed, AK2 knockdown leads to early and massive apoptosis of T-ALL cells that could not be rescued by the cytosolic isoform AK1. Mechanistically, AK2 depletion results in mitochondrial dysfunction marked by early mitochondrial depolarization and reactive oxygen species production, together with the depletion of antiapoptotic molecules (BCL-2 and BCL-XL). Finally, T-ALL exposure to a BCL-2 inhibitor (ABT-199 [venetoclax]) significantly enhances the cytotoxic effects of AK2 depletion. We also show that AK2 depletion disrupts the oxidative phosphorylation pathway. Combined with pharmaceutical inhibition of glycolysis, AK2 silencing prevents T-ALL metabolic adaptation, resulting in dramatic apoptosis. Altogether, we pinpoint AK2 as a genuine and promising therapeutic target in T-ALL.


Assuntos
Leucemia-Linfoma Linfoblástico de Células T Precursoras , Imunodeficiência Combinada Severa , Adenilato Quinase , Humanos , Mitocôndrias , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética
2.
Oncotarget ; 6(22): 18956-65, 2015 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-26068967

RESUMO

T-cell acute lymphoblastic leukemia (T-ALL) represents expansion of cells arrested at specific stages of thymic development with the underlying genetic abnormality often determining the stage of maturation arrest. Although their outcome has been improved with current therapy, survival rates remain only around 50% at 5 years and patients may therefore benefit from specific targeted therapy. Interleukin receptor associated kinase 1 (IRAK1) is a ubiquitously expressed serine/threonine kinase that mediates signaling downstream to Toll-like (TLR) and Interleukin-1 Receptors (IL1R). Our data demonstrated that IRAK1 is overexpressed in all subtypes of T-ALL, compared to normal human thymic subpopulations, and is functional in T-ALL cell lines. Genetic knock-down of IRAK1 led to apoptosis, cell cycle disruption, diminished proliferation and reversal of corticosteroid resistance in T-ALL cell lines. However, pharmacological inhibition of IRAK1 using a small molecule inhibitor (IRAK1/4-Inh) only partially reproduced the results of the genetic knock-down. Altogether, our data suggest that IRAK1 is a candidate therapeutic target in T-ALL and highlight the requirement of next generation IRAK1 inhibitors.


Assuntos
Quinases Associadas a Receptores de Interleucina-1/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/enzimologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Corticosteroides/farmacologia , Adulto , Apoptose/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Feminino , Técnicas de Silenciamento de Genes , Humanos , Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Quinases Associadas a Receptores de Interleucina-1/biossíntese , Quinases Associadas a Receptores de Interleucina-1/genética , Células Jurkat , Masculino , Terapia de Alvo Molecular , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Transdução de Sinais
3.
PLoS One ; 9(7): e103405, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25068647

RESUMO

Neuropilins and semaphorins are known as modulators of axon guidance, angiogenesis, and organogenesis in the developing nervous system, but have been recently evidenced as also playing a role in the immune system. Here we describe the expression and role of semaphorin 3F (SEMA3F) and its receptor neuropilin-2 (NRP2) in human T cell precursors. NRP2 and SEMA3F are expressed in the human thymus, in both lymphoid and non-lymphoid compartments. SEMA3F have a repulsive effect on thymocyte migration and inhibited CXCL12- and sphingosine-1-phosphate (S1P)-induced thymocyte migration by inhibiting cytoskeleton reorganization prior to stimuli. Moreover, NRP2 and SEMA3F are expressed in human T-cell acute lymphoblastic leukemia/lymphoma primary cells. In these tumor cells, SEMA3F also blocks their migration induced by CXCL12 and S1P. Our data show that SEMA3F and NRP2 are further regulators of human thymocyte migration in physiological and pathological conditions.


Assuntos
Movimento Celular/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Neuropilina-2/genética , Células Precursoras de Linfócitos T/metabolismo , Anticorpos Bloqueadores/imunologia , Anticorpos Bloqueadores/farmacologia , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Quimiocina CXCL12/farmacologia , Criança , Pré-Escolar , Expressão Gênica , Humanos , Lactente , Recém-Nascido , Lisofosfolipídeos/farmacologia , Proteínas de Membrana/metabolismo , Proteínas de Membrana/farmacologia , Microscopia Confocal , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/farmacologia , Neuropilina-2/imunologia , Neuropilina-2/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Esfingosina/análogos & derivados , Esfingosina/farmacologia , Timócitos/metabolismo , Timo/citologia , Timo/metabolismo
4.
Mol Cell Endocrinol ; 314(2): 244-7, 2010 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-19733621

RESUMO

Ghrelin and obestatin are two peptides isolated from the gastrointestinal tract and encoded by the same preproghrelin gene. They convey to the central nervous system informations concerning the nutritional status and/or the energy stores. Ghrelin, mostly acting through the GH secretagogue receptor GHS-R, is a potent GH secretagogue, an orexigenic peptide and a long-term regulator of energy homeostasis. Obestatin was initially described for its anorexigenic effects and its binding to the G protein-coupled receptor 39 (GPR39). However, the role of obestatin is still controversial and the nature of the obestatin receptor remains an open question. This review is focussed on the possible implication of the ghrelin/obestatin system in psychiatric diseases with particular emphasis on eating disorders.


Assuntos
Composição Corporal/fisiologia , Metabolismo Energético/fisiologia , Grelina/metabolismo , Animais , Retroalimentação Fisiológica/fisiologia , Humanos , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Grelina/metabolismo
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