Dataset Information

The genomics of acute myeloid leukemia in children.

ABSTRACT: Acute myeloid leukemia (AML) is a clinically, morphologically, and genetically heterogeneous disorder. Like many malignancies, the genomic landscape of pediatric AML has been mapped recently through sequencing of large cohorts of patients. Much has been learned about the biology of AML through studies of specific recurrent genetic lesions. Further, genetic lesions have been linked to specific clinical features, response to therapy, and outcome, leading to improvements in risk stratification. Lastly, targeted therapeutic approaches have been developed for the treatment of specific genetic lesions, some of which are already having a positive impact on outcomes. While the advances made based on the discoveries of sequencing studies are significant, much work is left. The biologic, clinical, and prognostic impact of a number of genetic lesions, including several seemingly unique to pediatric patients, remains undefined. While targeted approaches are being explored, for most, the efficacy and tolerability when incorporated into standard therapy is yet to be determined. Furthermore, the challenge of how to study small subpopulations with rare genetic lesions in an already rare disease will have to be considered. In all, while questions and challenges remain, precisely defining the genomic landscape of AML, holds great promise for ultimately leading to improved outcomes for affected patients.

SUBMITTER: Conneely SE

PROVIDER: S-EPMC7324027 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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The genomics of acute myeloid leukemia in children.

Conneely Shannon E SE Rau Rachel E RE

Cancer metastasis reviews 20200301 1

Acute myeloid leukemia (AML) is a clinically, morphologically, and genetically heterogeneous disorder. Like many malignancies, the genomic landscape of pediatric AML has been mapped recently through sequencing of large cohorts of patients. Much has been learned about the biology of AML through studies of specific recurrent genetic lesions. Further, genetic lesions have been linked to specific clinical features, response to therapy, and outcome, leading to improvements in risk stratification. Las ...[more]

PMID: 31925603

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Project description:Activity of the enzyme thiopurine methyltransferase (TPMT) determines the anti-leukemic effect of thiopurines used in the chemotherapy of acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML). TPMT status and its effects on treatment outcome have been studied extensively in ALL and autoimmune disorders, but few data is available on TPMT in AML. The present study assessed the genetic polymorphisms and activity of TPMT in children with AML at different treatment stages, and compared the results with those obtained for children with ALL. The study included 33 children with AML (0.7-19.7 years) treated with 6-thioguanine (6-TG) according to the AML-BFM 2004 Protocol. Blood samples were collected at diagnosis, during and following maintenance chemotherapy from 8, 10 and 17 patients with AML (the assay was performed at two time points in 2 patients), respectively. Blood samples from 105 children with ALL were obtained at diagnosis, during the maintenance chemotherapy and following the cessation of the chemotherapy from 16, 55 and 34 children, respectively. The activity of TPMT in red blood cells lysates was measured using an enzymatic reaction based on the conversion of 6-mercaptopurine into 6-methylmercaptopurine, involving S-adenozyl-L-methionine as the methyl group donor. TPMT mutations were determined using a polymerase chain reaction/restriction fragment length polymorphism method. Median TPMT activity at diagnosis, during maintenance chemotherapy and following chemotherapy was 43.1, 47,3 and 41.7 nmol 6-mMP g-1 Hb h-1, respectively. All patients with AML exhibited the homozygous TPMT*1/*1 genotype, with the exception of 1, who was a heterozygote with the TPMT*1/*3C genotype and demonstrated a TPMT activity level at diagnosis of 42.5 nmol 6-mMP g-1 Hb h-1. At each chemotherapy stage, the median TPMT activities in children with AML were significantly increased compared with the median TPMT activities in children with ALL. The preliminary results suggest that the TPMT activity in AML may be increased compared with that in ALL. Comprehensive studies on the association between thiopurine metabolism and treatment outcome in AML are required, with regard to the cytogenetic and molecular factors currently used for AML risk stratification.

Dataset Information

The genomics of acute myeloid leukemia in children.

Publications

The genomics of acute myeloid leukemia in children.

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