Significance of<i>CASP8AP2</i>and<i>H2AFZ</i>expression in survival and risk of relapse in children with acute lymphoblastic leukemia

Juárez-Velázquez, Rocío; Reyes-León, Adriana; Salas-Labadía, Consuelo; Rivera-Luna, Roberto; Velasco-Hidalgo, Liliana; López-Hernández, Gerardo; López-Santiago, Norma; Paredes‐Aguilera, Rogelio; Domínguez‐López, Aarón; Bernaldez, R; Pérez-Vera, Patricia

doi:10.3109/10428194.2013.878458

Cited by 16 publications

(18 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Accordingly, the genetic variation of the H2AFX promoter has been associated with the risk of glioma, particularly adult glioma [17]. On the other hand, the fusion of H2AFY with MDS1 and EVI1 Complex (MECOM) and the downregulation of H2AFZ have been associated with cancer progression in leukemia [18,19]. However, the clinical relevance of H2AFJ in cancers, including GBM, remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Histone 2A Family Member J Drives Mesenchymal Transition and Temozolomide Resistance in Glioblastoma Multiforme

Lee

Lin

et al. 2019

Cancers

View full text Add to dashboard Cite

Glioblastoma multiforme (GBM) is the most aggressive brain tumor and has a poor prognosis and is poorly sensitive to radiotherapy or temozolomide (TMZ) chemotherapy. Therefore, identifying new biomarkers to predict therapeutic responses of GBM is urgently needed. By using The Cancer Genome Atlas (TCGA) database, we found that the upregulation of histone 2A family member J (H2AFJ), but not other H2AFs, is extensively detected in the therapeutic-insensitive mesenchymal, IDH wildtype, MGMT unmethylated, or non-G-CIMP GBM and is associated with poor TMZ responsiveness independent of radiation. Similar views were also found in GBM cell lines. Whereas H2AFJ knockdown diminished TMZ resistance, H2AFJ overexpression promoted TMZ resistance in a panel of GBM cell lines. Gene set enrichment analysis (GSEA) revealed that H2AFJ upregulation accompanied by the activation of TNF-α/NF-κB and IL-6/STAT3-related pathways is highly predicted. Luciferase-based promoter activity assay further validated that the activities of NF-κB and STAT3 are causally affected by H2AFJ expression in GBM cells. Moreover, we found that therapeutic targeting HADC3 by tacedinaline or NF-κB by ML029 is likely able to overcome the TMZ resistance in GBM cells with H2AFJ upregulation. Significantly, the GBM cohorts harboring a high-level H2AFJ transcript combined with high-level expression of TNF-α/NF-κB geneset, IL-6/STAT3 geneset or HADC3 were associated with a shorter time to tumor repopulation after initial treatment with TMZ. These findings not only provide H2AFJ as a biomarker to predict TMZ therapeutic effectiveness but also suggest a new strategy to combat TMZ-insensitive GBM by targeting the interaction network constructed by TNF-α/NF-κB, IL-6/STAT3, HDAC3, and H2AFJ.

show abstract

Section: Introductionmentioning

confidence: 99%

Histone 2A Family Member J Drives Mesenchymal Transition and Temozolomide Resistance in Glioblastoma Multiforme

Lee

Lin

et al. 2019

Cancers

View full text Add to dashboard Cite

show abstract

“…22 In acute lymphoblastic leukemia patients, loss of FLASH expression was correlated with poor treatment response and relapse. 28, 29 However, an antiapoptotic role for FLASH has been described in studies showing that FLASH can suppress apoptosis in both Fas-dependent and -independent manners. 20, 25 These studies performed in fibrosarcoma cells and colorectal carcinoma cells suggest that FLASH can promote or inhibit apoptosis depending on the context and cell type involved.…”

Section: Discussionmentioning

confidence: 99%

FLASH protects ZEB1 from degradation and supports cancer cells' epithelial-to-mesenchymal transition

2016

Oncogenesis

View full text Add to dashboard Cite

Cancer metastasis remains a significant challenge and the leading cause of cancer-associated deaths. It is postulated that during metastasis cells undergo epithelial-to-mesenchymal transition (EMT), a process characterized by loss of cell–cell contacts and increased migratory and invasive potential. ZEB1 is one the most prominent transcriptional repressors of genes associated with EMT. We identified caspase-8-associated protein 2 (CASP8AP2 or FLASH) as a novel posttranscriptional regulator of ZEB1. Here we demonstrate that FLASH protects ZEB1 from proteasomal degradation brought by the action of the ubiquitin ligases SIAH1 and F-box protein FBXO45. As a result, loss of FLASH rapidly destabilized ZEB1 and reversed EMT cellular characteristics. Importantly, loss of FLASH blocked transforming growth factor-β-induced EMT and enhanced sensitivity to chemotherapy. Thus, we propose that FLASH–ZEB1 interplay may be a protective mechanism against ZEB1 degradation in cells undergoing EMT and may be an efficacious target for therapies aimed to block EMT progression.

show abstract

“…However, it is important to note that in addition to deaths caused by relapse, induction deaths also occurred, which could be related to other causes besides the response to treatment. Because minimal residual disease analysis is not accessible to all patients enrolled in the PMIP, it is essential for us to identify cases prone to relapse through potential risk markers such as the DNI of IKZF1 [ 17 ]. However, we did not find IKZF1 as an independent marker of relapse.…”

Section: Discussionmentioning

confidence: 99%

“…Leukemia was classified by immunophenotyping according to the following criteria: for B-ALL, cCD79a+, cCD22+ and CD19+ with additional analyses of CD34, TdT, CD10, CD20 and CD22; for T-ALL, cCD3+ and CD7+ with additional analysis of CD34, TdT, CD1, CD2, CD3 and CD5. The treatment protocols were based on the scheme of the PMIP for Mexican ALL-children that includes the following drugs: prednisone, L-asparaginase, vincristine, methotrexate, etoposide, cytosine arabinoside, 6-mercaptopurine, and doxorubicin [ 16 , 17 ].…”

Section: Methodsmentioning

confidence: 99%

“…The early identification of Ikaros non-functional isoforms as a prognostic marker could benefit those patients who initially are not classified in the high-risk group based on other conventional risk factors. The aim of this study was to detect the DNI Ik6 and Ik8, in Mexican ALL-children treated with the Public Medical Insurance Program (PMIP) [ 16 , 17 ], to know their frequency and association with conventional prognostic factors and adverse events, as well as to evaluate its usefulness in the initial stratification of patients and future therapeutic application.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Expression of Ik6 and Ik8 Isoforms and Their Association with Relapse and Death in Mexican Children with Acute Lymphoblastic Leukemia

et al. 2015

Self Cite

View full text Add to dashboard Cite

Expression of the 6 and 8 dominant-negative Ikaros isoforms in pediatric patients with acute lymphoblastic leukemia has been associated with a high risk of relapse and death; due to these isoforms disrupting the differentiation and proliferation of lymphoid cells. The aim of this study was to know the frequency of Ik6 and Ik8 in 113 Mexican ALL-children treated within the National Popular Medical Insurance Program to determine whether there was an association with relapse-free survival, event-free survival and overall survival, and to assess its usefulness in the initial stratification of patients. The expression of these isoforms was analyzed using specific primer sets and nested RT-PCR. The detected transcripts were classified according to the isoforms’s sizes reported. A non-expected band of 300 bp from one patient was analyzed by sequencing. Twenty-six patients expressed Ik6 and/or Ik8 and one of them expressed a variant of Ik8 denominated Ik8-deleted. Although the presence of them was not statistically associated with lower relapse free survival (p = 0.432), event free survival (p = 0.667) or overall survival (p = 0.531), inferior overall survival was observed in patients that expressed these isoforms and showed high or standard risk by age and white blood-cell count at diagnosis. Of the 26 patients Ik6+ and/or Ik8+, 14 did not present adverse events; from them 6 were exclusively Ik6+ and/or Ik8+, and 8 were positive for the other Ikaros isoforms (Ik1, Ik2, Ik5, Ik3A, Ik4, Ik4A, Ik7). In the patients studied, the expression of Ik6 and Ik8 did not constitute an independent prognostic factor for relapse or death related to disease; therefore, they could not be used in the initial risk stratification.

show abstract

Significance ofCASP8AP2andH2AFZexpression in survival and risk of relapse in children with acute lymphoblastic leukemia

Cited by 16 publications

References 30 publications

Histone 2A Family Member J Drives Mesenchymal Transition and Temozolomide Resistance in Glioblastoma Multiforme

Histone 2A Family Member J Drives Mesenchymal Transition and Temozolomide Resistance in Glioblastoma Multiforme

FLASH protects ZEB1 from degradation and supports cancer cells' epithelial-to-mesenchymal transition

Expression of Ik6 and Ik8 Isoforms and Their Association with Relapse and Death in Mexican Children with Acute Lymphoblastic Leukemia

Contact Info

Product

Resources

About