Low mRNA expression of the apoptosis‐related genes CASP3, CASP8, and FAS is associated with low induction treatment response in childhood acute lymphoblastic leukemia (ALL)

Mata, Juliana França da; Silveira, Vanessa da Silva; Mateo, Elvis Cristian Cueva; Cortez, María Angélica; Queiróz, Rosane Gomes de Paula; Yunes, José Andrés; Lee, Maria Lúcia de Martino; Toledo, Sílvia Regina Caminada de; Petrilli, Antônio Sérgio; Brandalise, Sílvia Regina; Tone, Luíz Gonzaga; Scrideli, Carlos Alberto

doi:10.1002/pbc.22463

Cited by 18 publications

(18 citation statements)

References 28 publications

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“…In agreement with our findings, the association of lower levels of CASP3 with a poor prognosis has been described in several human cancers including gastric carcinomas (22), ovarian carcinomas (23), hepatocellular carcinomas (24), childhood acute lymphoblastic leukemia (25), and esophageal cancer (26).…”

Section: Discussionsupporting

confidence: 79%

Expression profile of apoptosis-related genes in childhood adrenocortical tumors: low level of expression of BCL2 and TNF genes suggests a poor prognosis

Lorea

Moreno

Borges

et al. 2012

European Journal of Endocrinology

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Background: Impaired apoptosis has been implicated in the development of childhood adrenocortical tumors (ACT), although the expression of apoptosis-related gene expression in such tumors has not been reported. Methods: The mRNA expression levels of the genes CASP3, CASP8, CASP9, FAS, TNF, NFKB, and BCL2 were analyzed by quantitative real-time PCR in consecutive tumor samples obtained at diagnosis from 60 children with a diagnosis of ACT and in 11 non-neoplastic adrenal samples. BCL2 and TNF protein expression was analyzed by immunohistochemistry. Results: A significant association was observed between tumor size R100 g and lower expression levels of the BCL2 (PZ0.03) and TNF (PZ0.05) genes; between stage IV and lower expression levels of CASP3 (PZ0.008), CASP9 (PZ0.02), BCL2 (PZ0.002), TNF (PZ0.05), and NFKB (PZ0.03); Weiss score R3 and lower expression of TNF (PZ0.01); unfavorable event and higher expression values of CASP9 (PZ0.01) and lower values of TNF (PZ0.02); and death and lower expression of BCL2 (PZ0.04). Underexpression of TNF was associated with lower event-free survival in uni-and multivariate analyses (P!0.01). Similar results were observed when patients with Weiss score !3 were excluded. Conclusion: This study supports the participation of apoptosis-related genes in the biology and prognosis of childhood ACT and suggests the complex role of these genes in the pathogenesis of this tumor.

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Section: Discussionsupporting

confidence: 79%

Expression profile of apoptosis-related genes in childhood adrenocortical tumors: low level of expression of BCL2 and TNF genes suggests a poor prognosis

Lorea

Moreno

Borges

et al. 2012

European Journal of Endocrinology

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“…In many solid tumor entities such as neuroectodermal tumors, downregulation of caspase-8 is a frequent event in patients' tumors associated with drug resistance and poor prognosis (2,5,8). In line, high expression levels of caspase-8 mRNA were prognostically significant for favorable response to initial chemotherapy in childhood ALL (7,8).…”

Section: Caspase-8 Is Downregulated In a Subset Of Primary All Cellsmentioning

confidence: 63%

“…2). As patients carrying these tumor cells might be of high risk for poor response to initial polychemotherapy (7,8), they might benefit from strategies restoring the expression of caspase-8 protein. Therefore, we next asked, whether apoptosis resistance against cytotoxic drugs that depend on functional caspase-8 could be overcome by upregulation of epigenetically downregulated caspase-8.…”

Section: Mtx Upregulates Epigenetically Downregulated Caspase-8mentioning

confidence: 99%

“…For acute lymphoblastic leukemia (ALL), the role of caspase-8 remains poorly defined. Interestingly, a recent paper showed that in patients with childhood ALL, high mRNA levels of caspase-8 were predictive for a good initial response to polychemotherapy (8).…”

Section: Introductionmentioning

confidence: 99%

“…Demethylating agents such as azacythidine induce reexpression of caspase-8 and sensitize for caspase-8-dependent apoptosis (1,2). Loss or dysfunction of caspase-8 result in increased cellular transformation, enhanced tumor progression, poor response to chemotherapy, and impaired prognosis of patients of different cancer entities (4)(5)(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

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Important Role of Caspase-8 for Chemosensitivity of ALL Cells

Ehrhardt

Wachter

Maurer

et al. 2011

Clinical Cancer Research

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Purpose: Sensitivity of tumor cells toward chemotherapy mainly determines the prognosis of patients suffering from acute lymphoblastic leukemia (ALL); nevertheless, underlying mechanisms regulating chemosensitivity remain poorly understood. Here, we aimed at characterizing the role of caspase-8 for chemosensitivity of B-and T-ALL cells.Experimental Design: Primary tumor cells from children with ALL were evaluated for expression levels of the caspase-8 protein, were amplified in nonobese diabetic/severe combined immunodeficient mice, transfected with siRNA, and evaluated for their chemosensitivity in vitro.Results: Effective cell death in B-and T-ALL cells depended on the presence of caspase-8 for the majority of cytotoxic drugs routinely used in antileukemia treatment. Caspase-8 was activated independently from extrinsic apoptosis signaling. Accordingly in primary ALL cells, the expression level of caspase-8 protein correlated with cell death sensitivity toward defined cytotoxic drugs in vitro. In the subgroup of primary ALL cells, with low expression of caspase-8, methotrexate (MTX) upregulated the expression of caspase-8 mediated by the transcription factor p53, suggesting epigenetic silencing of caspase-8. RNA interference in patient-derived B-and T-ALL cells revealed that effective cell death induction by most routine drug combinations involving MTX depended on the presence of caspase-8.Conclusion: Our results indicate that caspase-8 is crucial for the high antileukemic efficiency of numerous routine cytotoxic drugs. Reexpression of epigenetically downregulated caspase-8 represents a promising approach to increase efficiency of antileukemic therapy. Clin Cancer Res; 17(24); 7605-13. Ó2011 AACR.

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MAPK/ERK and PI3K/AKT signaling pathways are activated in adolescent and adult acute lymphoblastic leukemia

Loureiro,

Bahia,

Lee

et al. 2023

Cancer Reports

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Background: The mitogen‐activated protein kinase (MAPK)/ERK signaling cascade and the phosphoinosytol‐3 phosphate/Akt (PI3K/Akt) pathways are involved in proliferation and differentiation of hematopoietic cells. The frequency of PI3K/Akt and MAPK pathway activation in adult acute lymphoblastic leukemia (ALL) still need to be elucidated.Aims: To assess the activity and prognostic implications of MAPK/ERK and PI3K/Akt pathways in adult (ALL).MethodsWe examined 28 precursor‐B‐cell ALL and 6 T‐cell primary ALL samples. Flow cytometry was employed to analyze the expression levels of phosphorylated ERK and phosphorylated Akt.ResultsTen out of 15 (67%) ALL fresh samples (7 B‐cell, 3 T‐cell) showed constitutive p‐ERK expression. The p‐ERK mean fluorescent index ratio (MFI (R)) showed a tendency to be higher in ALL than in normal T lymphocytes (1.26 [0.74–3.10] vs. 1.08 [1.02–1.21], respectively [p = .069]) and was significantly lower than in leukemic cell lines (median MFI (R) 3.83 [3.71–5.97] [p < .001]). Expression of p‐Akt was found in 35% (12/34) (10 B‐cell, 2 T‐cell). The median MFI (R) expression for p‐Akt in primary blast cell was 1.13 (0.48–9.90) compared to 1.01 (1.00–1.20) in normal T lymphocytes (p = ns) and lower than in leukemic cell lines (median MFI (R) 2.10 [1.77–3.40] [p = .037]). Moreover, expression of p‐ERK was negatively associated with the expression of CD34 (1.22 [0.74–1.33] vs. 1.52 [1.15–3.10] for CD34(+) and CD34(−) group, respectively, p = .009).ConclusionOur findings suggest that both MAPK/ERK and PI3K/Akt are constitutively activated in adult ALL, indicating a targeted therapy potential for ALL by using inhibitors of these pathways.

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Low mRNA expression of the apoptosis‐related genes CASP3, CASP8, and FAS is associated with low induction treatment response in childhood acute lymphoblastic leukemia (ALL)

Abstract: These findings suggest an association between lower expression levels of the pro-apoptotic genes and a poor response to induction therapy at day 7 and prognosis in childhood ALL.

Cited by 18 publications

References 28 publications

Expression profile of apoptosis-related genes in childhood adrenocortical tumors: low level of expression of BCL2 and TNF genes suggests a poor prognosis

Expression profile of apoptosis-related genes in childhood adrenocortical tumors: low level of expression of BCL2 and TNF genes suggests a poor prognosis

Important Role of Caspase-8 for Chemosensitivity of ALL Cells

MAPK/ERK and PI3K/AKT signaling pathways are activated in adolescent and adult acute lymphoblastic leukemia

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