MTHFR 677T-1298C haplotype in acute lymphoblastic leukemia: Impact on methotrexate therapy

2021 ◽  
pp. 107815522110171
Author(s):  
Rim Frikha ◽  
Moez Elloumi ◽  
Tarek Rebai ◽  
Hassen Kamoun
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Methylenetetrahydrofolate Reductase ◽  
Fragment Length Polymorphism ◽  
Lymphoblastic Leukemia ◽  
Allelic Frequency ◽  
Mthfr Gene ◽  
Methotrexate Therapy ◽  
Wild Type ◽  
Functional Variants ◽  
Toxicity Score

Introduction Functional variants of the Methylenetetrahydrofolate reductase ( MTHFR) gene, the C677T and A1298C, have largely investigated in pharmacogenomics of Methotrexate (MTX) in acute lymphoblastic leukemia (ALL), yet the conclusions are inconsistent. In addition; most of these studies do not analyze haplotypes. Here, we investigate the MTHFR 677/1298 genotypes and the 677-1298 haplotype and characterize the MTX response in Northern African ALL patients. Methods Genomic DNA was extracted from whole venous from a total of 28 patients with ALL. Genotyping were carried out with restriction fragment length polymorphism (RFLP). A toxicity score (TS) is calculated for each patient and correlate to the haplotype. Results The allelic frequency of MTHFR 677T-1298C haplotype was 10.7% in ALL patients. According to the toxicity’s score (TS) there was no significant differences between haplotype groups (p = 0.79): TS was higher with wild type of MTHFR (TS = 3.43; SEM ± 0.85) followed by combined genotype (677T-1298C) (TS = 2.67; SEM ± 0.88) and isolated variant (C677T or A1298C) (TS = 2.64; SEM ± 0.92). Conclusion Despite the limitation of this study; our results suggest that the MTHFR 677T-1298C haplotype is common in ALL and may be a promising HD-MTX chemotherapy-related adverse effects biomarker.

Role of MTHFR genetic polymorphisms in the susceptibility to childhood acute lymphoblastic leukemia

Blood ◽  
2004 ◽  
Vol 103 (1) ◽  
pp. 252-257 ◽  
Author(s):  
Maja Krajinovic ◽  
Stéphanie Lamothe ◽  
Damian Labuda ◽  
Émilie Lemieux-Blanchard ◽  
Yves Théorêt ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Methylenetetrahydrofolate Reductase ◽  
Lymphoblastic Leukemia ◽  
Protective Role ◽  
Mthfr Gene ◽  
Environment Interaction ◽  
Crude Odds Ratio ◽  
Childhood All ◽  
Mthfr Polymorphisms

Abstract The central role of methylenetetrahydrofolate reductase (MTHFR) in the folate metabolism renders MTHFR gene polymorphisms (C677T and A1298C) potential modulators of a variety of disorders whose development depends on folate/homocysteine imbalance. Here, we provide additional evidence on the protective role of these polymorphisms in acute lymphoblastic leukemia (ALL), the most common pediatric cancer. A case-control study was conducted in 270 ALL patients and 300 healthy controls of French-Canadian origin. The TT677/AA1298 and CC677/CC1298 individuals were associated with reduced risk of ALL (crude odds ratio [OR] = 0.4; 95% confidence interval [CI], 0.2-0.9; and OR = 0.3; 95% CI, 0.1-0.6; respectively). Further stratification in patients born before and after January 1996 (approximate time of Health Canada recommendation for folic acid supplement in pregnancy) revealed that the protective effect of MTHFR variants is accentuated and present only in children born before 1996. Similar results were obtained when a transmission disequilibrium test was performed on a subset of children (n = 95) in a family-based study. This finding suggests gene-environment interaction and its role in the susceptibility to childhood ALL, which is consistent with previous findings associating either folate deficiency or MTHFR polymorphisms with risk of leukemia.

scholarly journals Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia

2017 ◽  
Vol 69 (2) ◽  
pp. 239-246 ◽  
Author(s):  
Jelena Lazic ◽  
Nikola Kotur ◽  
Nada Krstovski ◽  
Lidija Dokmanovic ◽  
Branka Zukic ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Relapse Rate ◽  
Genetic Variants ◽  
Methylenetetrahydrofolate Reductase ◽  
Lymphoblastic Leukemia ◽  
Mthfr Gene ◽  
Specific Pcr ◽  
Reductase Gene ◽  
Pediatric All ◽  
Allele Specific

Despite remarkable progress in survival of children with acute lymphoblastic leukemia (ALL) which has reached about 85%, early toxicity and relapse rate remain issues that need to to be resolved. Genetic variants are important factors influencing the metabolism of cytotoxic drugs in ALL treatment. Variants in genes coding for methotrexate (MTX)-metabolizing enzymes are under constant scientific interest due to their potential impact on drug toxicity and relapse rate. We investigated methylenetetrahydrofolate reductase (MTHFR) c.677C>T and MTHFR c.1298A>C variants as pharmacogenetic markers of MTX toxicity and predictors of relapse. The study enrolled 161 children with ALL, treated according to the current International Berlin-Frankfurt-Munster group (BFM) for diagnostics and treatment of leukemia and lymphoma protocols. Genotyping was performed using PCRRFLP and allele-specific PCR assays. Our results revealed similar distributions of MTHFR c.677C>T and MTHFR c.1298A>C genotypes among 104 healthy individuals as compared to pediatric ALL patients. A lower incidence of early MTX toxicity was noted in the MTHFR c.677TT genotype (p=0.017), while MTHFR c.1298A>C genotypes were not associated with MTX toxicity. Carriers of any MTHFR c.677C>T and MTHFR c.1298A>C genotypes did not experience decreased overall survival (OAS) or higher relapse rates. Genetic variants in the MTHFR gene are not involved in leukemogenesis in pediatric ALL. The presence of the MTHFR c.677TT genotype was recognized as a predictive factor for decreased MTX toxicity during the intensification phase of therapy. Neither MTHFR c.677C>T nor MTHFR c.1298A>C genotypes correlated with an increased number of toxic deaths or relapse rate. Our study emphasizes the importance of implementing pharmacogenetic markers in order to optimize pediatric ALL therapy.

Do polymorphisms of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene affect the risk of childhood acute lymphoblastic leukemia?

2007 ◽  
Vol 21 (12) ◽  
pp. 885-886 ◽  
Author(s):  
Tiago Veiga Pereira ◽  
Martina Rudnicki ◽  
Alexandre Costa Pereira ◽  
Maria S. Pombo-de-Oliveira ◽  
Rendrik França Franco
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Methylenetetrahydrofolate Reductase ◽  
Lymphoblastic Leukemia ◽  
Mthfr Gene ◽  
Childhood Acute Lymphoblastic Leukemia

A novel PAX5-ELN fusion protein identified in B-cell acute lymphoblastic leukemia acts as a dominant negative on wild-type PAX5

Blood ◽  
2006 ◽  
Vol 109 (8) ◽  
pp. 3417-3423 ◽  
Author(s):  
Marina Bousquet ◽  
Cyril Broccardo ◽  
Cathy Quelen ◽  
Fabienne Meggetto ◽  
Emilienne Kuhlein ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Quantitative Polymerase Chain Reaction ◽  
Dominant Negative ◽  
Leukemic Cells ◽  
Dominant Negative Effect ◽  
Wild Type ◽  
Cell Acute Lymphoblastic Leukemia

Abstract We report a novel t(7;9)(q11;p13) translocation in 2 patients with B-cell acute lymphoblastic leukemia (B-ALL). By fluorescent in situ hybridization and 3′ rapid amplification of cDNA ends, we showed that the paired box domain of PAX5 was fused with the elastin (ELN) gene. After cloning the full-length cDNA of the chimeric gene, confocal microscopy of transfected NIH3T3 cells and Burkitt lymphoma cells (DG75) demonstrated that PAX5-ELN was localized in the nucleus. Chromatin immunoprecipitation clearly indicated that PAX5-ELN retained the capability to bind CD19 and BLK promoter sequences. To analyze the functions of the chimeric protein, HeLa cells were cotransfected with a luc-CD19 construct, pcDNA3-PAX5, and with increasing amounts of pcDNA3-PAX5-ELN. Thus, in vitro, PAX5-ELN was able to block CD19 transcription. Furthermore, real-time quantitative polymerase chain reaction (RQ-PCR) experiments showed that PAX5-ELN was able to affect the transcription of endogenous PAX5 target genes. Since PAX5 is essential for B-cell differentiation, this translocation may account for the blockage of leukemic cells at the pre–B-cell stage. The mechanism involved in this process appears to be, at least in part, through a dominant-negative effect of PAX5-ELN on the wild-type PAX5 in a setting ofPAX5 haploinsufficiency.

scholarly journals Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment

Genes ◽  
2020 ◽  
Vol 11 (4) ◽  
pp. 468
Author(s):  
Nikola Kotur ◽  
Jelena Lazic ◽  
Bojan Ristivojevic ◽  
Biljana Stankovic ◽  
Vladimir Gasic ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Allele Frequency ◽  
Methylenetetrahydrofolate Reductase ◽  
Lymphoblastic Leukemia ◽  
Statistical Modelling ◽  
Joint Effect ◽  
Allele Frequency Distribution ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Consolidation Phase ◽  
Pediatric All

Methotrexate (MTX) is one of the staples of pediatric acute lymphoblastic leukemia (ALL) treatment. MTX targets the folate metabolic pathway (FMP). Abnormal function of the enzymes in FMP, due to genetic aberrations, leads to adverse drug reactions. The aim of this study was to investigate variants in pharmacogenes involved in FMP and their association with MTX pharmacokinetics (MTX elimination profile) and toxicity in the consolidation therapy phase of pediatric ALL patients. Eleven variants in the thymidylate synthetase (TYMS), methylenetetrahydrofolate reductase (MTHFR), dihydrofolate reductase (DHFR), SLC19A1 and SLCO1B genes were analyzed in 148 patients, using PCR- and sequencing-based methodology. For the Serbian and European control groups, data on allele frequency distribution were extracted from in-house and public databases. Our results show that the A allele of SLC19A1 c.80 variant contributes to slow MTX elimination. Additionally, the AA genotype of the same variant is a predictor of MTX-related hepatotoxicity. Patients homozygous for TYMS 6bp deletion were more likely to experience gastrointestinal toxicity. No allele frequency dissimilarity was found for the analyzed variants between Serbian and European populations. Statistical modelling did not show a joint effect of analyzed variants. Our results indicate that SLC19A1 c.80 variant and TYMS 6bp deletion are the most promising pharmacogenomic markers of MTX response in pediatric ALL patients.

Successful Application of OPLS-DA for the Discrimination of Wild-Type and Mutated Cells in Acute Lymphoblastic Leukemia

2009 ◽  
Vol 28 (8) ◽  
pp. 822-828 ◽  
Author(s):  
Claudio Giuseppe Molteni ◽  
Giovanni Cazzaniga ◽  
Daniele F. Condorelli ◽  
Cosimo G. Fortuna ◽  
Andrea Biondi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Wild Type

Biopterin and neurotransmitter amine metabolism in children with acute lymphoblastic leukemia receiving methotrexate therapy

1986 ◽  
Vol 108 (3) ◽  
pp. 470-474 ◽  
Author(s):  
C.R. Pinkerton ◽  
I. Smith ◽  
R.J. Leeming ◽  
G. Sarna ◽  
K. Hyland ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Methotrexate Therapy ◽  
Amine Metabolism
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