Epigenetic deregulation in pediatric acute lymphoblastic leukemia

Chatterton, Zac; Morenos, Leah; Méchinaud, Françoise; Ashley, David M.; Craig, Jeffrey M; Sexton-Oates, Alexandra; Halemba, Minhee S.; Parkinson-Bates, Mandy; Ng, Jane; Morrison, Debra J.; Carroll, William L.; Saffery, Richard; Wong, Nicholas C.

doi:10.4161/epi.27585

Cited by 51 publications

(46 citation statements)

References 59 publications

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“…Genome-wide DNA methylation profiles are commonly altered in pediatric ALL (41). It has been demonstrated that hypermethylation of multiple genes may be involved in the relapse of childhood ALL (42).…”

Section: Discussionmentioning

confidence: 99%

FHIT promoter DNA methylation and expression analysis in childhood acute lymphoblastic leukemia

et al. 2017

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Abstract. Fragile histidine triad (FHIT) is a tumor suppressor gene, which is involved in several malignancies. Epigenetic alterations in FHIT have been hypothesized to contribute to tumorigenesis. The present study aimed to examine DNA promoter methylation and gene expression levels of FHIT in childhood acute lymphoblastic leukemia (ALL), in a sample of Iranian patients. The promoter methylation status of FHIT was analyzed in 100 patients diagnosed with ALL and 120 healthy control patients. mRNA expression levels were assessed in 30 new cases of ALL compared with 32 healthy controls. Hypermethylation of the FHIT promoter was significantly more frequent in patients with ALL than in healthy controls (OR=3.83, 95% CI=1.51-9.75, P=0.007). Furthermore, FHIT mRNA expression levels were significantly reduced in childhood ALL patients compared with healthy controls (P=0.032). The results of the present study revealed that dysregulation of the FHIT gene may contribute to the pathogenesis of childhood ALL. Future studies investigating a larger sample population with greater ethnic diversity would be beneficial, to confirm the results from the present study.

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Section: Discussionmentioning

confidence: 99%

FHIT promoter DNA methylation and expression analysis in childhood acute lymphoblastic leukemia

et al. 2017

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“…Finally, other epigenetic regulators, such as DNA methylation, histone modifications and long noncoding RNAs could also have a role in the development of L-ASP hypersensitivity. In this line, it has been already demonstrated that ALL ETV6-RUNX1 subtype displays hypermethylation of ASNS [91], which was associated with a higher sensitivity of leukemic cells to L-ASP [92] in ETV6-RUNX1 patients [93]. This developing field of pharmacoepigenetics has started to produce promising results and epigenetic variants have great potential to be used as biomarkers for personalized therapy.…”

Section: Conclusion and Future Perspectivementioning

confidence: 76%

Review of pharmacogenetics studies of L-asparaginase hypersensitivity in acute lymphoblastic leukemia points to variants in the GRIA1 gene

Lopez-Santillan

Iparraguirre

Martín-Guerrero

et al. 2017

Drug Metabolism and Personalized Therapy

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Acute lymphoblastic leukemia (ALL) is a major pediatric cancer in developed countries. Although treatment outcome has improved owing to advances in chemotherapy, there is still a group of patients who experience severe adverse events. L-Asparaginase is an effective antineoplastic agent used in chemotherapy of ALL. Despite its indisputable indication, hypersensitivity reactions are common. In those cases, discontinuation of treatment is usually needed and anti-asparaginase antibody production may also attenuate asparaginase activity, compromising its antileukemic effect. Till now, six pharmacogenetic studies have been performed in order to elucidate possible genetic predisposition for inter-individual differences in asparaginase hypersensitivity. In this review we have summarized the results of those studies which describe the involvement of four different genes, being polymorphisms in the glutamate receptor, ionotropic, AMPA 1 (GRIA1) the most frequently associated with asparaginase hypersensitivity. We also point to new approaches focusing on epigenetics that could be interesting for consideration in the near future.

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“…Such alterations represent underused biomarkers in oncology capable of discriminating cancers of different tissue types, subtyping cancers, and adding independent prognostic information to cancer diagnosis (18,19 ). Here we present 2 complementary techniques that enable (a) regional multiplexing of DNA methylation (multiplexed EpiTYPER) facilitating robust diagnosis/prognosis and subtyping and (b) detection of rare DNA methylation events (methylSABER) that will facilitate disease tracking.…”

Section: Discussionmentioning

confidence: 99%

Validation of DNA Methylation Biomarkers for Diagnosis of Acute Lymphoblastic Leukemia

et al. 2014

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BACKGROUND DNA methylation biomarkers capable of diagnosis and subtyping have been found for many cancers. Fifteen such markers have previously been identified for pediatric acute lymphoblastic leukemia (ALL). Validation of these markers is necessary to assess their clinical utility for molecular diagnostics. Substantial efficiencies could be achieved with these DNA methylation markers for disease tracking with potential to replace patient-specific genetic testing. METHODS We evaluated DNA methylation of promoter regions of TLX3 (T-cell leukemia homeobox) and FOXE3 (forkhead box E3) in bone marrow biopsies from 197 patients classified as leukemic (n = 95) or clear of the disease (n = 102) by MALDI-TOF. Using a single nucleotide extension assay (methylSABER), we tested 10 bone marrow biopsies collected throughout the course of patient chemotherapy. Using reference materials, diagnostic thresholds and limits of detection were characterized for both methods. RESULTS Reliable detection of DNA methylation of TLX3 and FOXE3 segregated ALL from those clear of disease with minimal false-negative and false-positive results. The limit of detection with MALDI-TOF was 1000–5000 copies of methylated allele. For methylSABER, the limit of detection was 10 copies of methylated TLX3, which enabled monitoring of minimal residual disease in ALL patients. CONCLUSIONS Mass spectrometry procedures can be used to regionally multiplex and detect rare DNA methylation events, establish DNA methylation loci as clinically applicable biomarkers for disease diagnosis, and track pediatric ALL.

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Epigenetic deregulation in pediatric acute lymphoblastic leukemia

Cited by 51 publications

References 59 publications

FHIT promoter DNA methylation and expression analysis in childhood acute lymphoblastic leukemia

FHIT promoter DNA methylation and expression analysis in childhood acute lymphoblastic leukemia

Review of pharmacogenetics studies of L-asparaginase hypersensitivity in acute lymphoblastic leukemia points to variants in the GRIA1 gene

Validation of DNA Methylation Biomarkers for Diagnosis of Acute Lymphoblastic Leukemia

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