Note | |
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Entity | t(6;11)(q15;q23) |
Disease | Acute myeloid leukemia. A t(6;11)(q15;q23) in a 50-year-old Korean woman with acute myeloid leukemia has been reported (Park TS et al., 2009). |
Hybrid/Mutated Gene | A MLL/CASP8AP2 fusion was identified by LDI-PCR and sequencing, a rearrangement between MLL (intron 8) and CASP8AP2 (intron 7) was detected at the genomic DNA level. The breakpoint analysis at the transcription level was not performed due to lack of a cDNA specimen |
Oncogenesis | MLL/CASP8AP2 seems to be related to poor clinical outcome, however, further studies are needed to evaluate prognosis. |
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Entity | Acute lymphoblastic leukemia |
Note | CASP8AP2 low expression |
Prognosis | The clinical significance of CASP8AP2 was first reported by (Flotho C et al., 2006), the differences in its expression levels were significantly associated with early response to treatment and the presence of minimal residual disease (MRD). CASP8AP2 expression was analyzed in 99 children with acute lymphoblastic leukemia (ALL) enrolled in the St. Jude Total Therapy Study XIII protocol. Patients with low levels of expression presented a lower event-free survival and higher incidence of relapse, in contrast to patients with higher expression levels. High expression was associated with greater propensity of leukemic cells to undergo apoptosis. In this study CASP8AP2 was considered as an independent prognostic marker for relapse (Flotho C et al., 2006). The usefulness of CASP8AP2 expression as a potential marker of response to treatment has been analyzed in leukemic patients from different populations. In a cohort of 39 newly diagnosed ALL children treated with the Beijing Children`s Hospital (BCH)-ALL 2003 protocol, the bone marrow expression of CASP8AP2 at diagnosis resulted a suitable indicator of relapse. In the same study, another cohort of 106 patients enrolled in the Chinese Childrens Leukemia Group (CCLG)-ALL 2008 protocol were also analyzed, patients with low CASP8AP2 expression showed higher relapse rates, lower relapse-free survival and lower overall-survival, in comparison to the higher-expression group (Jiao Y et al., 2012). ). In an independent study a gene signature of 14 genes, including CASP8AP2 and H2AFZ, was identified (Flotho C et al., 2007); their low expressions were associated to relapse. Based on this result, the expressions of CASP8AP2 and H2AFZ were analyzed in a cohort of 88 ALL Mexican children treated with the Popular Medical Insurance protocols (Juárez-Velázquez R et al., 2014). An increased risk for early relapse in patients with low expression of CASP8AP2 was found, confirming its usefulness as a risk marker; the H2AFZ expression did not showed the same effect. The CASP8AP2 expression was not an independent marker of relapse, but combined characteristics as the low expressions of both genes and high white blood cell count, identified more accurately patients at greater risk of relapse (Juárez-Velázquez R et al., 2014). Although the prognostic value of CASP8AP2 expression as an independent factor is controversial (Yang YL et al., 2010), combined with expressions of other genes such as H2AFZ (Juárez-Velázquez R et al., 2014) and ARS2 (Cui L et al., 2015), could more precisely predict high risk of relapse in ALL. ). Epigenetic modifications are also related to the down-regulation of CASP8AP2. DNA hypermethylation of the gene promoter was analyzed in 86 children with ALL, treated according to the BCH-2003 and CCLG-2008 protocols. The percentage of methylation of two CpG sites at positions -1189 and -1176 were inversely correlated with mRNA expression. The patients with higher methylation presented MRD and poor treatment outcome. The results suggested that combination of methylation level and MRD might improve current risk stratification (Li ZG et al., 2013). In regard to these findings, it has been demonstrated that methylation of the CASP8AP2 promoter in somatic stem cells and cancer cells increase their resistance to drugs (Lee KD et al., 2012). These data associate this epigenetic modification with the development of drug resistance. |
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Entity | T-cell acute lymphoblastic leukemia) (T-ALL) |
Note | A del(6)(q15-q16.1) has been reported in approximately 12% of T-ALL patients. This deletion includes the CASP8AP2 gene, whose mRNA expression was the single most down-regulated gene of all 7 genes located in the deleted region. |
Prognosis | The lower expression of CASP8AP2 has been also associated to deletions at band 6q15-q16.1, which are often detected in patients with T-ALL (Remke M et al., 2009). These deletions result in down regulation of the gene and poor early response to treatment. In 73 T-cell ALL samples obtained from patients enrolled in the multicenter ALL-BFM 1990, ALL-BFM 1995 and ALL-BFM 2000 protocols, deletion 6q15-q16.1 was associated with unfavorable MRD levels. Although deletion 6q15-q16.1 involves several genes, CASP8AP2 was the single one with a better association between the deletion and the less efficient induction of apoptosis by chemotherapy (Remke M et al., 2009). |
Cytogenetics | The del(6)(q15-q16.1)comprises 2.54 Mb. |
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Entity | Diffuse large B-cell lymphomas )( activated B-cell like subtype) |
Note | Loss of CASP8AP2 in 35% of cases. Imbalance with possible pathogenic relevance (Scholtysik R et al., 2015). |
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SUMO modification regulates the transcriptional activity of FLASH. |
Alm-Kristiansen AH, Norman IL, Matre V, Gabrielsen OS. |
Biochem Biophys Res Commun 2009; 387 (3): 494-499 |
PMID 19615980 |
|
FLASH Is Required for Histone Transcription and S-Phase Progression |
Barcaroli D, Bongiorno-Borbone L, Terrinoni A, Hofmann TG, Rossi M, Knight RA, Matera AG, Melino G, De Laurenzi V. |
Proc Natl Acad Sci U S A 2006; 103 (40): 14808-14812 |
PMID 17003125 |
|
Low Expressions of ARS2 and CASP8AP2 Predict Relapse and Poor Prognosis in Pediatric Acute Lymphoblastic Leukemia Patients Treated on China CCLG-ALL 2008 Protocol |
Cui L, Gao C, Zhang RD, Jiao Y, Li WJ, Zhao XX, Liu SG, Yue ZX, Zheng HY, Deng GR, Wu MY, Li ZG, Jia HT. |
Leuk Res 2015; 39 (2): 115-123 |
PMID 25530566 |
|
FLASH Is Essential during Early Embryogenesis and Cooperates with p73 to Regulate Histone Gene Transcription |
De Cola A, Bongiorno-Borbone L, Bianchi E, Barcaroli D, Carletti E, Knight RA, Di Ilio C, Melino G, Sette C, De Laurenzi v. |
Oncogene 2012; 31 (5): 573-582 |
PMID 21725362 |
|
A Set of Genes That Regulate Cell Proliferation Predicts Treatment Outcome in Childhood Acute Lymphoblastic Leukemia |
Flotho C, Coustan-Smith E, Pei D,Cheng C, Song G, Pui CH, Downing JR, Campana D. |
Blood 2007; 110 (4): 1271-1277 |
PMID 17456722 |
|
The CED-4-Homologous Protein FLASH Is Involved in Fas-Mediated Activation of Caspase-8 during Apoptosis |
Imai Y, Kimura T, Murakami A, Yajima N, Sakamaki K, Yonehara S. |
Nature 1999; 398 (6730): 777-785 |
PMID 10235259 |
|
CASP8AP2 Is a Promising Prognostic Indicator in Pediatric Acute Lymphoblastic Leukemia |
Jiao Y, Cui L, Gao C, Li W, Zhao X, Liu S, Wu M, Deng G, Li Z. |
Leuk Res 2012; 36 (1): 67-71 |
PMID 21696825 |
|
Significance of CASP8AP2 and H2AFZ Expression in Survival and Risk of Relapse in Children with Acute Lymphoblastic Leukemia |
Juárez-Velázquez R, Reyes-León A, Salas-Labadèa C, Rivera-Luna R, Velasco-Hidalgo L, López-Hernández G, López-Santiago N, Paredes-Aguilera R, Domènguez-López A, Bernáldez R, Pérez-Vera P. |
Leuk Lymphoma 2014; 55 (10): 2305-2311 |
PMID 24397596 |
|
Tumor Necrosis Factor Alpha Receptor- and Fas-Associated FLASH Inhibit Transcriptional Activity of the Glucocorticoid Receptor by Binding to and Interfering with Its Interaction with p160 Type Nuclear Receptor Coactivators |
Kino T, Chrousos GP. |
J Biol Chem 2003 ; 278 (5): 3023-3029 |
PMID 12477726 |
|
Interaction of FLASH with Arsenite Resistance Protein 2 Is Involved in Cell Cycle Progression at S Phase |
Kiriyama M, Kobayashi Y, Saito M, Ishikawa F, Yonehara S. |
Mol Cell Biol 2009; 29 (17): 4729-4741 |
PMID 19546234 |
|
Targeted Casp8AP2 Methylation Increases Drug Resistance in Mesenchymal Stem Cells and Cancer Cells |
Lee KD, Pai MY, Hsu CC, Chen CC, Chen YL, Chu PY, Lee CH, Chen LT, Chang JY,Huang TH, Hsiao SH, Leu YW. |
Biochem Biophys Res Commun 2012; 422 (4): 578-585 |
PMID 22595458 |
|
Hypermethylation of Two CpG Sites Upstream of CASP8AP2 Promoter Influences Gene Expression and Treatment Outcome in Childhood Acute Lymphoblastic Leukemia |
Li ZG, Jiao Y, Li WJ, Deng GR, Cui L, Gao C, Zhao XX, Wu MY, Jia HT. |
Leuk Res 2013; 37 (10): 1287-1293 |
PMID 23953914 |
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CASP8AP2 Is a Novel Partner Gene of MLL Rearrangement with t(6;11)(q15;q23) in Acute Myeloid Leukemia |
Park TS, Lee SG, Song J, Lee KA, Kim J, Choi JR, Lee ST, Marschalek R, Meyer C. |
Cancer Genet Cytogenet 2009; 195 (1): 94-95 |
PMID 19837277 |
|
High-Resolution Genomic Profiling of Childhood T-ALL Reveals Frequent Copy-Number Alterations Affecting the TGF-Beta and PI3K-AKT Pathways and Deletions at 6q15-16.1 as a Genomic Marker for Unfavorable Early Treatment Response |
Remke M, Pfister S, Kox C, Toedt G, Becker N, Benner A, Werft W, Breit S, Liu S, Engel F, Wittmann A, Zimmermann M, Stanulla M, Schrappe M, Ludwig WD, Bartram CR, Radlwimmer B, Muckenthaler MU, Lichter P, Kulozik AE. |
Blood 2009; 114 (5): 1053-1062 |
PMID 19406988 |
|
Characterization of genomic imbalances in diffuse large B-cell lymphoma by detailed SNP-chip analysis |
Scholtysik R, Kreuz M, Hummel M, Rosolowski M, Szczepanowski M, Klapper W, Loeffler M, Trümper L, Siebert R, Küppers R; Molecular Mechanisms in Malignant Lymphomas Network Project of the Deutsche Krebshilfe. |
Int J Cancer 2015; 136(5): 1033-1042. |
PMID 25042405 |
|
FLASH, a Proapoptotic Protein Involved in Activation of Caspase-8, Is Essential for 3' End Processing of Histone Pre-mRNAs |
Yang XC, Burch BD, Yan Y, Marzluff WF, Dominski Z. |
Mol Cell 2009; 36 (2): 267-278 |
PMID 19854135 |
|
Expression and Prognostic Significance of the Apoptotic Genes BCL2L13, Livin, and CASP8AP2 in Childhood Acute Lymphoblastic Leukemia |
Yang YL, Lin SR, Chen JS, Lin SW, Yu SL, Chen HY, Yen CT, Lin CY, Lin JF, Lin KH, Jou ST, Hu CY, Chang SK, Lu MY, Chang HH, Chang WH, Lin KS, Lin DT. |
Leuk Res 2010; 34 (1): 18-23 |
PMID 20109966 |
|