Project description:try to find out the genetic sites (genotype) relevant to child bone marrow suppression induced by mercaptopurine. It is a research in pharmacogenomics and precision medicine, which aims to treat each patient individually.

2020-01-19 | E-MTAB-8613 | biostudies-arrayexpress

Expression data of plasma microRNA from the healthy children and children who diagnosed with acute lymphoblastic leukemia

Project description:According to the status of children acute lymphoblastic leukemia,we collected samples from the new dignosed, complete remmission and relapsed.

2018-01-31 | GSE109868 | GEO

Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia.

Project description:PurposeMercaptopurine (MP) is the mainstay of curative therapy for acute lymphoblastic leukemia (ALL). We performed a genome-wide association study (GWAS) to identify comprehensively the genetic basis of MP intolerance in children with ALL.Patients and methodsThe discovery GWAS and replication cohorts included 657 and 371 children from two prospective clinical trials. MP dose intensity was a marker for drug tolerance and toxicities and was defined as prescribed dose divided by the planned protocol dose during maintenance therapy; its association with genotype was evaluated using a linear mixed-effects model.ResultsMP dose intensity varied by race and ethnicity and was negatively correlated with East Asian genetic ancestry (P < .001). The GWAS revealed two genome-wide significant loci associated with dose intensity: rs1142345 in TPMT (Tyr240Cys, present in *3A and *3C variants; P = 8.6 × 10(-9)) and rs116855232 in NUDT15 (P = 8.8 × 10(-9)), with independent replication. Patients with TT genotype at rs116855232 were exquisitely sensitive to MP, with an average dose intensity of 8.3%, compared with those with TC and CC genotypes, who tolerated 63% and 83.5% of the planned dose, respectively. The NUDT15 variant was most common in East Asians and Hispanics, rare in Europeans, and not observed in Africans, contributing to ancestry-related differences in MP tolerance. Of children homozygous for either TPMT or NUDT15 variants or heterozygous for both, 100% required ≥ 50% MP dose reduction, compared with only 7.7% of others.ConclusionWe describe a germline variant in NUDT15 strongly associated with MP intolerance in childhood ALL, which may have implications for treatment individualization in this disease.

| S-EPMC4375304 | biostudies-literature

Optimal predictor for 6-mercaptopurine intolerance in Chinese children with acute lymphoblastic leukemia: NUDT15, TPMT, or ITPA genetic variants?

Project description:BACKGROUND:6-mercaptopurine (6-MP) contributes substantially to remarkable improvement in the survival of childhood acute lymphoblastic leukemia (ALL) patients. However, 6-MP also has dose-limiting toxicities, particularly life-threatening myelosuppression, due to genetic polymorphisms in enzymes that metabolize 6-MP. Promising biomarkers for predicting 6-MP-induced leukopenia is still unclear in Chinese population. Here, we evaluated the associations of NUDT15, TPMT and ITPA genotypes with 6-MP intolerance in our cohort of childhood ALL patients. METHODS:A total of 105 Chinese pediatric patients with a confirmed diagnosis of ALL were enrolled. We identified the NUDT15 coding variant rs116855232 (c.415C?>?T), a newly discovered 6-MP toxicity-related locus in Asians, and polymorphisms in TPMT rs1142345 and ITPA rs11273540. Associations between genotypes and 6-MP dose sensitivity, leukopenia, hepatotoxicity, and therapy interruption were evaluated. RESULTS:The minor allele frequencies (MAFs) of NUDT15 rs116855232, TPMT rs1142345 and ITPA rs11273540 were 15.7, 2.9, and 18.1%, respectively. NUDT15 and TPMT genetic variants were strongly associated with 6-MP dose intensity. Patients with NUDT15 homogenous genotype (TT) were highly sensitive to 6-MP (dose intensity of 60.27%) compared to these with heterozygous genotype (TC) or wild type (CC), who tolerated an average dose intensity of 83.83 and 94.24%, respectively. The NUDT15 variant was a predictor for leukopenia (OR: 3.62, 95% CI 1.377-9.501, P?=?0.009) and early-onset leukopenia (OR: 9.63, 95% CI 2.764-33.514, P?=?3.75?×?10-?4). No differences were found between 6-MP dose intensity and ITPA polymorphisms. CONCLUSION:NUDT15 variant is an optimal predictor for 6-MP intolerance in Chinese pediatric ALL patients and may have greatly clinical implications for individualized therapy.

| S-EPMC5932771 | biostudies-literature

Transcriptomic profiling of 2 cell lines from Down-Syndrome children with Acute Lymphoblastic Leukaemia (DS-ALL)

Project description:Two cell lines derived from 2 Down Syndrome children who developed Acute Lymphoblastic Leukaemia were profiled at the transcriptomic level (bulk RNAseq) and compared against their Patient-Derived Xenograft (PDX) of origin.

2024-07-10 | GSE245056 | GEO

Transcription profiling of human leukemia cells treated with mercaptopurine and/or methotrexate

Project description:To elucidate the genomics of cellular responses to cancer treatment, we analyzed the expression of over 9,600 human genes in acute lymphoblastic leukemia cells before and after in vivo treatment with methotrexate and mercaptopurine given alone or in combination. Based on changes in gene expression, we identified 124 genes that accurately discriminated among the four treatments. Discriminating genes included those involved in apoptosis, mismatch repair, cell cycle control and stress response. Only 14% of genes that changed when these medications were given as single agents also changed when they were given together. These data indicate that lymphoid leukemia cells of different molecular subtypes share common pathways of genomic response to the same treatment, that changes in gene expression are treatment-specific and that gene expression can illuminate differences in cellular response to drug combinations versus single agents.

2007-12-13 | E-GEOD-412 | biostudies-arrayexpress

Gene expression profiling of children affected by acute lymphoblastic leukemia

Project description:We have examined gene expression profiling of 18 children with acute lymphoblastic leukemia (ALL). In particular, the ALL patients are subdivided in three different subtypes by morphological, immunophenotypic and cytogenetical parameters: 10 ALL-B, 5 ALL-T and 3 ALL-B with the specific chromosomal aberration MLL/AF4. We compared the transcription profiles of the leukemic samples by microarray competitive hybridization against an arbitrary total RNA reference prepared from normal human bone marrow. Two replicates of each experiment were done using different microarray slides, in which the sample and reference RNAs labeled either with Cy3 or Cy5 fluorochromes were crossed in both combinations. ALL-B patients: GSM49966, GSM49967, GSM49969, GSM49970, GSM49971, GSM49972, GSM49973, GSM49974, GSM49976, GSM49977, GSM49978, GSM49979, GSM49980, GSM49981, GSM49982, GSM49983, GSM49984, GSM49985, GSM49986, GSM49987 ALL-T patients: GSM49988, GSM49989, GSM49990, GSM49991, GSM49992, GSM49993, GSM49994, GSM49995, GSM49996, GSM49997 ALL-B patients with the specific chromosomal aberration MLL/AF4: GSM49999, GSM50001, GSM50004, GSM50005, GSM50006, GSM50007 Keywords = Acute lymphoblastic leukemia (ALL) Keywords = human bone marrow Keywords = gene expression profiling Reference: Haematologica 2005;90:890-898 Keywords: ordered

2005-07-04 | GSE2604 | GEO

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