The Relationship Between Thiopurine Methyltransferase Activity and Genotype in Blasts From Patients With Acute Leukemia

Blood ◽  
1998 ◽  
Vol 92 (8) ◽  
pp. 2856-2862 ◽  
Author(s):  
Sally A. Coulthard ◽  
Christopher Howell ◽  
Jill Robson ◽  
Andrew G. Hall
Keyword(s):  
Genetic Basis ◽  
Lymphoblastic Leukemia ◽  
Cell Activity ◽  
Leukemic Cell ◽  
Tpmt Activity ◽  
Thiopurine Methyltransferase ◽  
Polymerase Chain ◽  
American Society ◽  
The Relationship ◽  
Reduced Activity

Abstract The level of expression of the enzyme thiopurine methyltransferase (TPMT) is an important determinant of the metabolism of thiopurines used in the treatment of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Studies in red blood cells (RBC) have shown that TPMT expression displays genetic polymorphism with 11% of individuals having intermediate and one in 300 undetectable levels. The genetic basis for this polymorphism has now been elucidated and polymerase chain reaction (PCR)-based assays described for the most common mutations accounting for reduced activity. In previous studies, genotype has been correlated with red blood cell activity. In this report, we describe the relationship between genotype and TPMT activity measured directly in the target of drug action, the leukemic cell. We have demonstrated that the TPMT activity in lymphoblasts from 38 children and adults found by PCR to be homozygotes (*1/*1) was significantly higher than that in the five heterozygotes (*1/*3) detected (median, 0.25 v 0.08, P < .002, Mann-Whitney U). Similar results were obtained when results from children were analyzed separately. However, comparison of activity in blasts from AML and ALL showed a higher level in the former (0.35 v 0.22 nU/mg,P < .002, n = 17, 35), suggesting that factors other than genotype may also influence expression. © 1998 by The American Society of Hematology.

The Relationship Between Thiopurine Methyltransferase Activity and Genotype in Blasts From Patients With Acute Leukemia

Blood ◽  
1998 ◽  
Vol 92 (8) ◽  
pp. 2856-2862
Author(s):  
Sally A. Coulthard ◽  
Christopher Howell ◽  
Jill Robson ◽  
Andrew G. Hall
Keyword(s):  
Genetic Basis ◽  
Lymphoblastic Leukemia ◽  
Cell Activity ◽  
Leukemic Cell ◽  
Tpmt Activity ◽  
Thiopurine Methyltransferase ◽  
Polymerase Chain ◽  
American Society ◽  
The Relationship ◽  
Reduced Activity

The level of expression of the enzyme thiopurine methyltransferase (TPMT) is an important determinant of the metabolism of thiopurines used in the treatment of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Studies in red blood cells (RBC) have shown that TPMT expression displays genetic polymorphism with 11% of individuals having intermediate and one in 300 undetectable levels. The genetic basis for this polymorphism has now been elucidated and polymerase chain reaction (PCR)-based assays described for the most common mutations accounting for reduced activity. In previous studies, genotype has been correlated with red blood cell activity. In this report, we describe the relationship between genotype and TPMT activity measured directly in the target of drug action, the leukemic cell. We have demonstrated that the TPMT activity in lymphoblasts from 38 children and adults found by PCR to be homozygotes (*1/*1) was significantly higher than that in the five heterozygotes (*1/*3) detected (median, 0.25 v 0.08, P < .002, Mann-Whitney U). Similar results were obtained when results from children were analyzed separately. However, comparison of activity in blasts from AML and ALL showed a higher level in the former (0.35 v 0.22 nU/mg,P < .002, n = 17, 35), suggesting that factors other than genotype may also influence expression. © 1998 by The American Society of Hematology.

scholarly journals Detection of the molecular abnormality in chronic myeloid leukemia by use of the polymerase chain reaction

Blood ◽  
1988 ◽  
Vol 72 (6) ◽  
pp. 2063-2065
Author(s):  
A Dobrovic ◽  
KJ Trainor ◽  
AA Morley
Keyword(s):  
Polymerase Chain Reaction ◽  
Chronic Myeloid Leukemia ◽  
Blood Cells ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cell ◽  
Great Sensitivity ◽  
Chain Reaction ◽  
Molecular Abnormality ◽  
Polymerase Chain

The bcr-abl translocation characteristic of chronic myeloid leukemia (CML) was detected by the polymerase chain reaction (PCR) modified to use mRNA as the starting material. Amplification of a sequence spanning the bcr-abl junction was obtained by using peripheral blood cells from all of 20 patients with classic CML, one patient with acute lymphoblastic leukemia probably secondary to CML, and two cell lines derived from patients with CML. The presence of bcr exon 3 in the mRNA was determined from the size of the amplified sequence; it was present in 14 and absent in seven patients. One leukemic cell per 1,000 nonleukemic cells could be readily detected, thus indicating the great sensitivity of the method. This technique is of routine value in CML both for diagnosis and for following the course of treatment.

scholarly journals Polymorphic thiopurine methyltransferase in erythrocytes is indicative of activity in leukemic blasts from children with acute lymphoblastic leukemia

Blood ◽  
1995 ◽  
Vol 85 (7) ◽  
pp. 1897-1902 ◽  
Author(s):  
HL McLeod ◽  
MV Relling ◽  
Q Liu ◽  
CH Pui ◽  
WE Evans
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Tpmt Activity ◽  
Severe Toxicity ◽  
Recessive Trait ◽  
Thiopurine Methyltransferase ◽  
Biochemical Basis ◽  
Intrapatient Variability ◽  
Relationship Of ◽  
Risk Of Treatment

The activity of thiopurine methyltransferase (TPMT) exhibits genetic polymorphism, with approximately 1 in 300 individuals inheriting TPMT deficiency as an autosomal recessive trait, and about 11% having intermediate activity (ie, heterozygotes). Patients with TPMT deficiency accumulate excessive concentrations of 6-thioguanine nucleotides (TGNs) and develop severe toxicity when treated with standard dosages of mercaptopurine. High TPMT activity has been associated with lower concentrations of TGNs, yielding a higher risk of treatment failure in children with acute lymphoblastic leukemia (ALL). As the biochemical basis of these pharmacodynamic relationships has not been fully elucidated, we investigated the variability and relationship of TPMT activity in erythrocytes and lymphoblasts from children with ALL. A 58-fold range of erythrocyte TPMT activity was found among 119 patients receiving ALL chemotherapy (0.6 to 34.9 U/mL packed erythrocytes), but relatively low intrapatient variability (coefficient of variation, 13.5%) was observed over 1 year. A 27-fold range in TPMT activity was observed in leukemic blasts obtained from 42 patients at initial diagnosis (3.3 to 88.9 U/1 x 10(9) cells). TPMT activity in leukemic blasts at diagnosis was significantly correlated with TPMT in erythrocytes before therapy (rs = .75, P < .0001, N = 13). These data document extensive interpatient variability of TPMT activity in ALL blasts and establish its linkage to polymorphic TPMT activity in erythrocytes, providing a new mechanism by which erythrocytes serve as prognostic markers of mercaptopurine metabolism and TPMT activity in children with ALL.

Thiopurine methyltransferase genetics is not a major risk factor for secondary malignant neoplasms after treatment of childhood acute lymphoblastic leukemia on Berlin-Frankfurt-Münster protocols

Blood ◽  
2009 ◽  
Vol 114 (7) ◽  
pp. 1314-1318 ◽  
Author(s):  
Martin Stanulla ◽  
Elke Schaeffeler ◽  
Anja Möricke ◽  
Sally A. Coulthard ◽  
Gunnar Cario ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Malignant Neoplasm ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Tpmt Activity ◽  
Malignant Neoplasms ◽  
Thiopurine Methyltransferase ◽  
Childhood All ◽  
Increased Risk ◽  
Secondary Malignant Neoplasm

AbstractThiopurine methyltransferase (TPMT)is involved in the metabolism of thiopurines such as 6-mercaptopurine and 6-thioguanine. TPMT activity is significantly altered by genetics, and heterozygous and even more homozygous variant people reveal substiantially decreased TPMT activity. Treatment for childhood acute lymphoblastic leukemia (ALL) regularly includes the use of thiopurine drugs. Importantly, childhood ALL patients with low TPMT activity have been considered to be at increased risk of developing therapy-associated acute myeloid leukemia and brain tumors. In the present study, we genotyped 105 of 129 patients who developed a secondary malignant neoplasm after ALL treatment on 7 consecutive German Berlin-Frankfurt-Münster trials for all functionally relevant TPMT variants. Frequencies of TPMT variants were similarly distributed in secondary malignant neoplasm patients and the overall ALL patient population of 814 patients. Thus, TPMT does not play a major role in the etiology of secondary malignant neoplasm after treatment for childhood ALL, according to Berlin-Frankfurt-Münster strategies.

scholarly journals Detection of the molecular abnormality in chronic myeloid leukemia by use of the polymerase chain reaction

Blood ◽  
1988 ◽  
Vol 72 (6) ◽  
pp. 2063-2065 ◽  
Author(s):  
A Dobrovic ◽  
KJ Trainor ◽  
AA Morley
Keyword(s):  
Polymerase Chain Reaction ◽  
Chronic Myeloid Leukemia ◽  
Blood Cells ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cell ◽  
Great Sensitivity ◽  
Chain Reaction ◽  
Molecular Abnormality ◽  
Polymerase Chain

Abstract The bcr-abl translocation characteristic of chronic myeloid leukemia (CML) was detected by the polymerase chain reaction (PCR) modified to use mRNA as the starting material. Amplification of a sequence spanning the bcr-abl junction was obtained by using peripheral blood cells from all of 20 patients with classic CML, one patient with acute lymphoblastic leukemia probably secondary to CML, and two cell lines derived from patients with CML. The presence of bcr exon 3 in the mRNA was determined from the size of the amplified sequence; it was present in 14 and absent in seven patients. One leukemic cell per 1,000 nonleukemic cells could be readily detected, thus indicating the great sensitivity of the method. This technique is of routine value in CML both for diagnosis and for following the course of treatment.

MiR-125a-5p Alleviates Dysfunction and Inflammation of Pentylenetetrazol- induced Epilepsy Through Targeting Calmodulin-dependent Protein Kinase IV (CAMK4)

2019 ◽  
Vol 16 (4) ◽  
pp. 365-372 ◽  
Author(s):  
Qishuai Liu ◽  
Li Wang ◽  
Guizhen Yan ◽  
Weifa Zhang ◽  
Zhigang Huan ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Target Gene ◽  
Luciferase Assay ◽  
Enzyme Linked Immunosorbent Assay ◽  
Inflammatory Factor ◽  
Dependent Protein Kinase ◽  
Expression Levels ◽  
Dependent Protein ◽  
Polymerase Chain ◽  
The Relationship

Background: MicroRNAs (miRNA) are known to play a key role in the etiology and treatment of epilepsy through controlling the expression of gene. However, miR-125a-5p in the epilepsy is little known. Epilepsy in rat models was induced by Pentylenetetrazol (PTZ) and miR- 125a-5p profiles in the hippocampus were investigated in our experiment. Also, the relationship between miR-125a-5p and calmodulin-dependent protein kinase IV (CAMK4) was identified and the related mechanism was also illustrated. Methods: The miR-125a-5p mRNA expression levels were evaluated by quantitative real time polymerase chain reaction (qRT-PCR). Western Blot (WB) was used to analyze the CAMK4 protein expression levels. Seizure score, latency and duration were determined based on a Racine scale. The enzyme-linked immunosorbent assay (ELISA) was used to analyze the inflammatory factor expression. The relationship between miR-125a-5p and CAMK4 was detected through dual luciferase assay. Results: Downregulation of miR-125a-5p was observed in the hippocampus of PTZ-induced epilepsy rats. The overexpression of miR-125a-5p attenuated seizure and decreased inflammatory factor level in the hippocampus of PTZ-induced rats. The miR-125a-5p alleviated epileptic seizure and inflammation in PTZ-induced rats by suppressing its target gene, CAMK4. Conclusion: miR-125a-5p may represent a novel therapeutic treatment for PTZ-induced epilepsy by preventing the activation of CAMK4.

scholarly journals Knockdown of Circ_SLC39A8 protects against the progression of osteoarthritis by regulating miR-591/IRAK3 axis

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Jizhe Yu ◽  
Yushuang Qin ◽  
Naxin Zhou
Keyword(s):  
Cell Viability ◽  
Molecular Mechanisms ◽  
Interleukin 1 ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Circular Rnas ◽  
Oa Chondrocytes ◽  
Polymerase Chain ◽  
Apoptosis And Inflammation ◽  
The Relationship

Abstract Background The dysregulation of circular RNAs (circRNAs) has been identified in various human diseases, including osteoarthritis (OA). The purpose of this study was to identify the role and mechanism of circ_SLC39A8 in regulating the progression of OA. Methods The expression levels of circ_SLC39A8, miR-591, and its potential target gene, interleukin-1-receptor-associated kinase 3 (IRAK3), were identified by quantitative real-time polymerase chain reaction (qRT-PCR). Cell viability and apoptosis were determined by Cell Counting Kit-8 (CCK-8) assay and flow cytometry, respectively. The relationship between miR-591 and circ_SLC39A8 or IRAK3 was predicted by bioinformatics tools and verified by dual-luciferase reporter. Results Circ_SLC39A8 and IRAK3 were upregulated and miR-591 was downregulated in OA cartilage tissues. Knockdown of circ_SLC39A8 inhibited apoptosis and inflammation in OA chondrocytes, while these effects were reversed by downregulating miR-591. Promotion cell viability effects of miR-591 were partially reversed by IRAK3 overexpression. Conclusion Our findings indicated that knockdown of circ_SLC39A8 delayed the progression of OA via modulating the miR-591-IRAK3 axis, providing new insight into the molecular mechanisms of OA pathogenesis.

scholarly journals Decitabine shows anti-acute myeloid leukemia potential via regulating the miR-212-5p/CCNT2 axis

2020 ◽  
Vol 15 (1) ◽  
pp. 1013-1023
Author(s):  
Lina Xing ◽  
Jinhai Ren ◽  
Xiaonan Guo ◽  
Shukai Qiao ◽  
Tian Tian
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Viability ◽  
Cell Apoptosis ◽  
Myeloid Leukemia ◽  
Luciferase Reporter ◽  
Expression Levels ◽  
Proliferation And Apoptosis ◽  
Polymerase Chain ◽  
The Relationship ◽  
Acute Myeloid

AbstractPrevious research has revealed the involvement of microRNA-212-5p (miR-212-5p) and cyclin T2 (CCNT2) in acute myeloid leukemia (AML). However, whether the miR-212-5p/CCNT2 axis is required for the function of decitabine in AML has not been well elucidated. Quantitative reverse transcription-polymerase chain reaction was used to examine enrichment of miR-212-5p. The relationship between CCNT2 and miR-212-5p was verified by the luciferase reporter assay. Cell apoptosis was evaluated by flow cytometry and western blot. CCK-8 assay was performed to determine cell viability. Decitabine significantly repressed cell viability, while promoted cell apoptosis. Meanwhile, the expression levels of cyclinD1, CDK4, and Bcl-2 were suppressed in cells with decitabine exposure, but Bax and caspase-3 expression levels were upregulated. Besides, miR-212-5p upregulation had the similar function with decitabine in AML cell proliferation and apoptosis. Subsequently, restoration of CCNT2 attenuated miR-212-5p overexpression-induced effects in Kasumi-1 and SKNO-1 cells. In addition, miR-212-5p depletion reversed decitabine-induced CCNT2 downregulation. The miR-212-5p/CCNT2 axis had an implication in the anti-leukemic effect of decitabine in AML.

The Relationship of the −5, −8, and −24 Variant Alleles in African Americans to Triosephosphate Isomerase (TPI) Enzyme Activity and to TPI Deficiency

Blood ◽  
1998 ◽  
Vol 92 (8) ◽  
pp. 2959-2962 ◽  
Author(s):  
Arthur Schneider ◽  
Linda Forman ◽  
Beryl Westwood ◽  
Catherine Yim ◽  
James Lin ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
African American ◽  
African Americans ◽  
Triosephosphate Isomerase ◽  
Small Subset ◽  
Nucleotide Substitutions ◽  
Severe Deficiency ◽  
American Society ◽  
Relationship Of ◽  
The Relationship

Abstract In 424 African-American and 75 white subjects, we found that the −5 (TPI 592 A→G), −8 (TPI 589 G→A), and −24 (TPI 573 T→G) variants in the triosephosphate isomerase (TPI) gene occurred frequently (41.0%) in the African-American subjects but did not occur in the whites. These data suggest that this set of polymorphisms may turn out to be one of the higher-incidence molecular markers of African lineage, a surprising finding because others had reported that these nucleotide substitutions were restricted to a small subset of African Americans who had been characterized as TPI-deficiency heterozygotes. Additionally, we investigated the relationship of these variants to TPI-enzyme activity. Although the variant substitutions (occurring in three haplotypes: −5 alone, −5 −8, and −5 −8 −24) were associated with moderate reduction in enzyme activity, severe-deficiency heterozygotes could not be identified with certainty, and none of the haplotypes were restricted to subjects with marked reduction of enzyme activity. Three subjects were homozygous for the −5 −8 haplotype, a finding inconsistent with the putative role of this haplotype as the cause of a null variant incompatible with life in homozygotes. Despite these findings, the possibility remains that the −5 −8 or −5 −8 −24 haplotypes may in some instances contribute to compound heterozygosity and clinical TPI deficiency. © 1998 by The American Society of Hematology.

The ABCs of Immunotherapy for Adult Patients With B-Cell Acute Lymphoblastic Leukemia

2017 ◽  
Vol 52 (3) ◽  
pp. 268-276 ◽  
Author(s):  
Troy Z. Horvat ◽  
Amanda N. Seddon ◽  
Adebayo Ogunniyi ◽  
Amber C. King ◽  
Larry W. Buie ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Data Extraction ◽  
Lymphoblastic Leukemia ◽  
Adult Patients ◽  
Efficacy And Safety ◽  
Car T Cells ◽  
Car T ◽  
American Society

Objective: To review the pharmacology, efficacy, and safety of Food and Drug Administration approved and promising immunotherapy agents used in the treatment of acute lymphoblastic leukemia (ALL). Data Sources: A literature search was performed of PubMed and MEDLINE databases (1950 to July 2017) and of abstracts from the American Society of Hematology and the American Society of Clinical Oncology. Searches were performed utilizing the following key terms: rituximab, blinatumomab, inotuzumab, ofatumumab, obinutuzumab, Blincyto, Rituxan, Gazyva, Arzerra, CAR T-cell, and chimeric antigen receptor (CAR). Study Selection/Data Extraction: Studies of pharmacology, clinical efficacy, and safety of rituximab, ofatumumab, obinutuzumab, inotuzumab, blinatumomab, and CAR T-cells in the treatment of adult patients with ALL were identified. Data Synthesis: Conventional chemotherapy has been the mainstay in the treatment of ALL, producing cure rates of approximately 90% in pediatrics, but it remains suboptimal in adult patients. As such, more effective consolidative modalities and novel therapies for relapsed/refractory disease are needed for adult patients with ALL. In recent years, anti-CD20 antibodies, blinatumomab, inotuzumab, and CD19-targeted CAR T-cells have drastically changed the treatment landscape of B-cell ALL. Conclusion: Outcomes of patients with relapsed disease are improving thanks to new therapies such as blinatumomab, inotuzumab, and CAR T-cells. Although the efficacy of these therapies is impressive, they are not without toxicity, both physical and financial. The optimal sequencing of these therapies still remains a question.

Sign in / Sign up

Export Citation Format

Share Document