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Blood Adv ; 3(13): 1981-1988, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31270080


Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) is a phosphatase known to be a tumor suppressor gene in T-cell acute lymphoblastic leukemia (T-ALL). Because the full clinicobiologic characteristics of PTPN2 loss remain poorly reported, we aimed to provide a comprehensive analysis of PTPN2 deletions within a cohort of 430 patients, including 216 adults and 214 children treated according to the GRAALL03/05 (#NCT00222027 and #NCT00327678) and the FRALLE2000 protocols, respectively. We used multiplex ligation-dependent probe amplification to identify an 8% incidence of PTPN2 deletion, which was comparable in adult (9%) and pediatric (6%) populations. PTPN2 deletions were significantly associated with an αß lineage and TLX1 deregulation. Analysis of the mutational genotype of adult T-ALL revealed a positive correlation between PTPN2 deletions and gain-of-function alterations in the IL7R/JAK-STAT signaling pathway as well as PHF6 and WT1 mutations. Of note, PTPN2 and PTEN (phosphatase and tensin homolog) deletions were mutually exclusive. Regarding treatment response, PTPN2-deleted T-ALLs were associated with a higher glucocorticoid response and a trend for improved survival in children, but not in adults, with a 5-year cumulative incidence of relapse of 8% for PTPN2-deleted pediatric cases vs 26% (P = .177).

Clin Cancer Res ; 25(8): 2483-2493, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30659025


PURPOSE: Biological explanation for discrepancies in patient-related response to chemotherapy depending on the underlying oncogenic events is a promising research area. TLX1- or TLX3-deregulated T-cell acute lymphoblastic leukemias (T-ALL; TLX1/3+) share an immature cortical phenotype and similar transcriptional signatures. However, their prognostic impacts differ, and inconsistent clinical outcome has been reported for TLX3. We therefore hypothesized that the overlapping transcriptional profiles of TLX1+ and TLX3+ T-ALLs would allow identification of candidate genes, which might determine their distinct clinical outcomes. EXPERIMENTAL DESIGN: We compared TLX1+ and TLX3+ adult T-ALL outcome in the successive French national LALA-94 and GRAALL-2003/2005 multicentric trials and analyzed transcriptomic data to identify differentially expressed genes. Epigenetic regulation of asparagine synthetase (ASNS) and in vitro l-asparaginase sensitivity were evaluated for T-ALL cell lines and primary samples. RESULTS: We show that TLX1+ patients expressed low levels of ASNS when compared with TLX3+ and TLX-negative patients, due to epigenetic silencing of ASNS by both DNA methylation and a decrease of active histone marks. Promoter methylation of the ASNS gene correlated with l-asparaginase sensitivity in both T-ALL cell lines and patient-derived xenografts. Finally, ASNS promoter methylation was an independent prognostic factor for both event-free survival [HR, 0.42; 95% confidence interval (CI), 0.24-0.71; P = 0.001] and overall survival (HR, 0.40; 95% CI, 0.23-0.70; P = 0.02) in 160 GRAALL-2003/2005 T-ALL patients and also in an independent series of 47 LL03-treated T lymphoblastic lymphomas (P = 0.012). CONCLUSIONS: We conclude that ASNS methylation status at diagnosis may allow individual adaptation of l-asparaginase dose.

Exp Gerontol ; 96: 146-154, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28676373


RATIONALE: In a recent systematic review, aging has been identified as the only factor independently associated with mortality during human acute respiratory distress syndrome (ARDS). We explored this age-dependent severity in a clinically relevant double hit murine ARDS model. METHODS: Young adult (Y, 10-12weeks) and middle-old (O, 12-13months) male C57BL6 mice underwent an aspiration of Escherichia coli lipopolysaccharide (LPS) or control saline vehicle. Twenty hours later, four groups of mice were sacrificed [Y(control), O(control), Y(LPS) and O(LPS)]. Four other groups of mice underwent 3h of low tidal volume (8mL/kg) mechanical ventilation (MV) [Y(MV), O(MV), Y(LPS+MV) and O(LPS+MV)]. Lung mechanics were assessed hourly during MV. Right ventricular pressure and cardiac output were measured at the end of the MV. After sacrifice, lung inflammation, edema and injury were explored with bronchoalveolar lavage (BAL) and histology. RESULTS: After saline aspiration, middle-old mice had a higher respiratory system compliance than young adult mice. LPS aspiration dramatically altered the baseline compliance in middle-old (O(LPS)), but not in young adult (Y(LPS)) mice. Middle-old mice had a more pronounced alteration in lungs mechanics during MV as compared to young adult mice. Lung inflammation (as assessed by the total cell count, IL-6, TNFα and MIP-2 concentrations in BAL fluid), systemic inflammation (as assessed by plasma IL-6 concentration) and alveolocapillary leak (as assessed by the total protein concentration of BAL fluid) were higher in O(LPS) and O(LPS+MV) mice as compared to Y(LPS) and Y(LPS+MV) mice, respectively. The combination of LPS+MV induced a higher lung injury as compared to LPS alone in middle-old mice but not in young adult mice. Hemodynamics (systemic blood pressure, cardiac output and pulmonary vascular resistances) were similar between Y(MV) and O(MV) on the one hand and between Y(LPS+MV) and O(LPS+MV) on the other hand. CONCLUSION: Middle-old mice were more susceptible to both LPS alone and the combination of LPS and low tidal volume MV as compared to their young adult counterparts. The synergism between LPS and MV was amplified in middle-old mice.

Envelhecimento/fisiologia , Síndrome do Desconforto Respiratório do Adulto/fisiopatologia , Lesão Pulmonar Aguda/fisiopatologia , Animais , Líquido da Lavagem Broncoalveolar/química , Modelos Animais de Doenças , Suscetibilidade a Doenças , Escherichia coli , Lipopolissacarídeos/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Pneumonia/fisiopatologia , Edema Pulmonar/fisiopatologia , Respiração Artificial/efeitos adversos , Testes de Função Respiratória , Resistência Vascular/fisiologia
Am J Respir Cell Mol Biol ; 56(5): 597-608, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28125278


Monocytes/macrophages are major effectors of lung inflammation associated with various forms of pulmonary hypertension (PH). Interactions between the CCL2/CCR2 and CX3CL1/CX3CR1 chemokine systems that guide phagocyte infiltration are incompletely understood. Our objective was to explore the individual and combined actions of CCL2/CCR2 and CX3CL1/CX3CR1 in hypoxia-induced PH in mice; particularly their roles in monocyte trafficking, macrophage polarization, and pulmonary vascular remodeling. The development of hypoxia-induced PH was associated with marked increases in lung levels of CX3CR1, CCR2, and their respective ligands, CX3CL1 and CCL2. Flow cytometry revealed that both inflammatory Ly6Chi and resident Ly6Clo monocyte subsets exhibited sustained increases in blood and a transient peak in lung tissue, and that lung perivascular and alveolar macrophage counts showed sustained elevations. CX3CR1-/- mice were protected against hypoxic PH compared with wild-type mice, whereas CCL2-/- mice and double CX3CR1-/-/CCL2-/- mice exhibited similar PH severity, as did wild-type mice. The protective effects of CX3CR1 deficiency occurred concomitantly with increases in lung monocyte and macrophage counts and with a change from M2 to M1 macrophage polarization that markedly diminished the ability of conditioned media to induce pulmonary artery smooth muscle cell (PA-SMC) proliferation, which was partly dependent on CX3CL1 secretion. Results in mice given the CX3CR1 inhibitor F1 were similar to those in CX3CR1-/- mice. In conclusion, CX3CR1 deficiency protects against hypoxia-induced PH by modulating monocyte recruitment, macrophage polarization, and PA-SMC cell proliferation. Targeting CX3CR1 may hold promise for treating PH.

Quimiocina CCL2/metabolismo , Quimiocina CX3CL1/metabolismo , Hipertensão Pulmonar/metabolismo , Pulmão/patologia , Receptores CCR2/metabolismo , Receptores de Quimiocinas/metabolismo , Animais , Receptor 1 de Quimiocina CX3C , Movimento Celular , Deleção de Genes , Hipertensão Pulmonar/complicações , Hipóxia/complicações , Hipóxia/metabolismo , Ligantes , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Fenótipo , Artéria Pulmonar/patologia
Oncotarget ; 6(22): 18956-65, 2015 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-26068967


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.

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