The Experience on Multiparametric Molecular Diagnostic Approach of Pediatric Acute Lymphoblastic Leukemia (ALL) in Greece.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4448-4448
Author(s):  
Agapi Parcharidou ◽  
Constantina Sambani ◽  
Christina Stavropoulou ◽  
George Paterakis ◽  
Chrysoula Belesi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Genetic Polymorphism ◽  
Lymphoblastic Leukemia ◽  
Molecular Diagnostic ◽  
Detoxifying Enzymes ◽  
Dna Index ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
In Vitro Chemosensitivity ◽  
Pediatric All

Abstract The rate of success in the treatment of pediatric acute lymphoblastic leukemia (ALL) has been increased steadily during the last decades. The five years’ event free survival rate is nearly 80% for children with ALL. Attempts to boost cure rates further with the use of hematopoietic stem cell transplantation have improved for some but not all, subtypes of ALL. The best hope for continued progress lies in a better understanding of the pathogenesis, the basis of resistance to chemotherapy, and finally better organized clinical trials. The present study has been based on organizing and exploring new clinical correlations among clinical data obtained from molecular genetic profile, in vitro chemosensitivity and genetic polymorphisms of detoxifying enzymes. During the last 3 years 43 newly diagnosed ALL patients, 27 boys and 16 girls, aged 23 months to 14 years old were included in this study. Bone marrow and/or peripheral blood samples were studied for karyotyping aberrations. The presence of the specific translocations t(12;21), t(9;22), t(4;11) and t(1;19) was investigated using RT-PCR and FISH. Furthermore, FISH was also used for the detection 9p deletions and MLL rearrangements. Immunophenotype of blasts and DNA index were studied by flow cytometry. In vitro chemosensitivity studies were performed by the MTT assay (ELISA).The GSTT1 genetic polymorphism (null genotype) was detected by multiplex PCR and NQ1 genetic polymorphism was detected by PCR -RFLPs. A cytogenetic/molecular result was achieved in 39/43 patients. Structural or numerical aberrations were detected in 7/39 patients. 9/39 patients were positive for the TEL/AML1 (23%) and 3/39 for the BCR/ABL fusion genes. One patient showed only one MLL allele, no patient had MLL rearrangement and 5/19 patients presented 9p deletion. A null GSTT1 genotype was observed in 5/43children (11,62%) and 14/43 patients were heterozygotes for NQ1(32,5%). 8/36 patients presented in vitro chemoresistance and 8/43 patients had DNA index >1 (18,6%).In our series of patients the frequency of t(12;21) does not seem to differ significantly from the literature data. The patients who showed chemoresistance had also unfavorable prognostic markers according to cytogenetic/molecular diagnostic data or clinical characteristics. The number of the patients is low to correlate detoxifying enzymes to toxicity or response during treatment. The multiparametric diagnostic approaches in pediatric ALL seem to be of great importance in diagnosis and tailored therapy leading to high rates of cure. Our center’s effort is the optimal characterization of the pediatric ALL profile in Greece by the use of multiparametric diagnostic methods targeting a better outcome.

In-Vitro Efficacy of the Deoxyguanoside Analogs Forodesine (BCX-1777) and ARA-G in Pediatric Acute Lymphoblastic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2038-2038
Author(s):  
Irene Homminga ◽  
Michel C. Zwaan ◽  
Amel Seghouani ◽  
Chantal Y. Manz ◽  
Shanta Bantia ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Nucleoside Transporter ◽  
Nucleotide Synthesis ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Expression Levels ◽  
Lc50 Value ◽  
Pediatric All

Abstract Abstract 2038 Poster Board II-15 Purine nucleoside phosphorylase (PNP) deficiency in humans is associated with elevated deoxyguanosine (dGuo) plasma levels. DGuo is converted into dGTP inducing apoptosis in T-cells and this provides the rationale for the development of deoxyguanosine analogues as a potential treatment option for T-cell malignancies. Forodesine (BCX-1777; BioCryst-Mundipharma) is an efficient blocker of PNP activity, thereby boosting the conversion of dGuo into dGTP and raising intracellular dGTP levels. AraG (9-b-D-arabinofuranosyl-guanine) is a compound that is resistant to PNP-mediated degradation that is efficiently converted into AraGTP. AraGTP becomes incorporated in the DNA, blocking DNA synthesis and promoting apoptosis. In a phase II clinical trial, the AraG prodrug Nelarabine enforced a complete remission rate of 55% for pediatric T-ALL patients at 1st relapse. (Berg, JCO 2005). Clinical data of Forodesine treatment in pediatric ALL patients are not yet available. As tested on primary pediatric acute lymphoblastic leukemia (ALL) patient samples (4 T-ALL, 2 BCP-ALL), 1μM of Forodesine is sufficient to completely block PNP and abolish rapid dGuo degradation resulting in a median 7.9 (range 0.5-378) fold raise of intracellular dGTP levels. Accumulation of dGTP is comparable for T-ALL (n=31) and BCP-ALL (n=11) patient samples. This reflects equal intrinsic ability of salvage nucleotide synthesis for both T-ALL and BCP-ALL cells. Cytotoxic effect of Forodesine was tested on primary leukemia cells from newly diagnosed pediatric ALL patients in-vitro by incubating cells with Forodesine (1μM) in the presence of increasing concentrations of dGuo (0.001-50μM). In accordance with selective T-cell toxicity, T-ALL cells were more sensitive to Forodesine/dGuo treatment (median T-ALL LC50 value: 1.1μM dGuo/1μM Forodesine, n=27, p=0.001) compared to BCP-ALL cells, which had a median LC50 value of 8.8μM dGuo/1μM Forodesine (n=30). All patients that responded demonstrated dGTP accumulation (1.5-222.1 fold), although the raise of dGTP levels did not correlate with Forodesine/dGuo toxicity (r2= 0.10, p=0.22). Studying in-vitro responsiveness to AraG, T-ALL cells were more sensitive compared to BCP-ALL cells (p=0.0002) with a median AraG LC50 value of 20.5μM for T-ALL samples (n=24) versus 48.3μM for BCP-ALL samples (n=20). Remarkably, TELAML1 positive BCP-ALL cases were insensitive to AraG treatment (median LC50 value >50μM, n=9). No correlation was identified between in-vitro Forodesine/dGuo and AraG cytotoxicities (r2=0.05, p=0.29). Most patient samples that displayed AraG resistance still responded to Forodesine/dGuo treatment. This may be explained by the fact that the uptake of both drugs may be facilitated by different transporters. Using RQ-PCR we could demonstrate that AraG toxicity, in contrast to Forodesine, was significantly associated with ENT1 (equilibrative nucleoside transporter 1) expression levels (p=0.008), which was previously identified as strong predictor for AraC cytotoxicity in pediatric ALL (Stam RW. et al., Blood 2003). AraG cytotoxicity strongly correlated with AraC cytotoxicity (r2=0.71, p<0.0001). We found no significant correlation between Forodesine sensitivity and the expression levels of other nucleoside transporters (CNT1, CNT2, CNT3, ENT2), kinases (dCK, dGK), nucleotidases (NT5C1A, NT5C2, PNI) or other enzymes that are involved in dGuo metabolism (PNP, RRM1, RRM2). In conclusion, T-ALL cells are more sensitive to Forodesine/dGuo treatment in-vitro than BCP-ALL cells that have nearly 8 fold higher dGuo LC50 values. Resistance to AraG treatment does not preclude responsiveness to Forodesine treatment and vice versa, indicating that Forodesine and AraG rely on different cellular mechanisms for cytotoxicity, possibly involving differences in dependence on the nucleoside transporter ENT1. Disclosures: No relevant conflicts of interest to declare.

In-Vitro Efficacy of the Deoxyguanoside Analogs Forodesine (BCX- 1777) and ARA-G in Pediatric Acute Lymphoblastic Leukemia Cells.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1925-1925
Author(s):  
Irene Homminga ◽  
Christian M Zwaan ◽  
Chantal Y. Manz ◽  
Shanta Bantia ◽  
Cynthia Parker ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Leukemia Cells ◽  
Nucleotide Synthesis ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Lc50 Value ◽  
Pediatric All

Abstract Purine nucleotide phosphorylase (PNP) deficiency in humans is associated with elevated dGuo plasma levels. This results in the intra-cellular conversion of dGuo into dGTP, following 3 consecutive kinase steps and depletion of T-cells resulting in immune deficiency. This T-cell toxicity provided the rationale for the development of deoxyguanosine analogues as potential therapeutic compounds for T-cell malignancies. Forodesine (BCX-1777; BioCryst-Mundipharma) is an efficient blocker of PNP activity. Forodesine facilitates the conversion of dGuo into dGTP raising the intracellular dGTP pool. AraG (9-b-D-arabinofuranosyl-guanine) is a compound that is resistant to PNP-mediated degradation resulting in phosphorylation of AraG into AraGTP. AraGTP becomes incorporated in the DNA and blocks DNA synthesis resulting in apoptosis. In a phase II clinical trial, the AraG prodrug Nelarabine enforced a complete remission rate of 55% for pediatric T-ALL patients at 1st relapse. (Berg, JCO 2005). Clinical data of forodesine treatment in pediatric ALL patients are not yet available. The cytotoxic effect of Forodesine was investigated on primary leukemia cells from newly diagnosed pediatric acute lymphoblastic leukemia (ALL) patients in-vitro. Cells were incubated with a fixed concentration of Forodesine (1μM) in the presence of increasing concentrations of dGuo (0.001–50μM). The dGTP levels under conditions where PNPactivity was completely blocked was monitored. Incubation of primary leukemic cells obtained from 6 pediatric ALL patients (4 T-ALL, 2 B-ALL) with 10μM dGuo results in rapid dGuo degradation (t½&lt;4hrs) by the PNP enzyme that is completely abolished by the addition of 1μM of Forodesine. Cells consequently accumulate dGTP levels upon Forodesine treatment to a median 7.9 (range 0.5–378 fold) that is comparable between T-ALL (n=31) and B-ALL (n=11) patient samples. This reflects equal intrinsic ability of de-novo nucleotide synthesis for both T-ALL and B-ALL cells. In accordance with T-cell selective toxicity, T-ALL cells were more sensitive to Forodesine/ dGuo treatment (median T-ALL LC50 value: 1.1μM dGuo/1μM Forodesine, n=27, p=0.001) compared to B-ALL cells, which had a median LC50 value of 8.8μM dGuo/1μM Forodesine (n=30). All patients that responded demonstrated dGTP accumulation (1.5– 222.1 fold), but the magnitude of dGTP accumulation did not relate to Forodesine/dGuo toxicity. Studying in-vitro responsiveness to AraG, T-ALL cells were more sensitive compared to B-ALL cells (p=0.0002) with a median AraG LC50 value of 20.5μM for T-ALL samples (n=24) versus 48.3μM for B-ALL samples (n=20). However, TELAML1 negative B-ALL cases were sensitive to AraG where as TELAML1 positive B-ALL cases were remarkable insensitive to AraG treatment (median LC50 value &gt;50μM, n=9). No correlation was identified between in-vitro Forodesine/dGuo and AraG cytotoxicities. Most patient samples that displayed AraG resistance still responded to Forodesine/dGuo treatment. In contrast, AraG cytotoxicity strongly correlated with AraC cytotoxicity (r2=0.71, p&lt;0.0001). In conclusion, T-ALL cells are sensitive to Forodesine/dGuo treatment in-vitro in contrast to B-ALL cells that have nearly 8 fold higher LC50 values. In-vitro Forodesine mediated cytotoxicity seems more potent in pediatric ALL than AraG treatment. Resistance to AraG treatment does not preclude responsiveness to Forodesine treatment and vice versa, indicating that Forodesine and AraG rely on different cellular mechanisms for cytotoxicity.

Role of Matrix Metalloproteinase MMP-2, MMP-9 and Tissue Inhibitor of Metalloproteinase (TIMP-1) in Clinical Progression of Pediatric Acute Lymphoblastic Leukemia

2021 ◽  
Author(s):  
Maha Saleh ◽  
Mohamed Khalil ◽  
Mona S. Abdellateif ◽  
Emad Ebeid ◽  
Eman Z. Kandeel
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Cell Count ◽  
Cancer Progression ◽  
Lymphoblastic Leukemia ◽  
Multivariate Logistic Regression Analysis ◽  
Blast Cell ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Tissue Inhibitor ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Pediatric All

Abstract Background: Matrix metalloproteinases (MMPs) play a crucial role in cancer progression and metastasis, however their role in pediatric Acute lymphoblastic leukemia (ALL) is still unrevealed.Methods: The diagnostic, prognostic and predictive value of tissue inhibitor of metalloproteinase (TIMP-1), MMP-2, MMP-9 and CD34+CD38- CSCs were assessed in bone marrow (BM) samples of 76 ALL children using Flow Cytometry analysis. Results: There was a significant increase in TIMP-1 [1.52 (0.41-10) versus 0.91(0.6-1.12); respectively, P<0.001], and CSCs CD84+CD38- [1 (0.03-18.6) versus 0.3 (0.01-1.1), P<0.001] expression in ALL patients compared to controls. While there were no significant differences regarding MMP-2 and MMP-9 expression between the two groups. The sensitivity, specificity, AUC of MMP-2 were (80.3%, 53.3% and 0.568, P=0.404), and that of MMP-9 were (53.9%, 40% and 0.660, P=0.053). While that of TIMP-1 were (78.9%, 100% and 0.892, P<0.001), and that of CSCs CD34+ CD38- were (78.9%, 73.3% and 0.855, P<0.001). There was a significant association between MMP-2 overexpression and MRD at day-15, increased BM blast cell count at diagnosis and at day-15, (P=0.020, P=0.047 and P=0.001). Increased TIMP-1 expression associated with the high-risk disease (P<0.001), increased BM blast cell count at diagnosis and at day-15 (P=0.033 and P=0.001), as well as MRD at day 15 and day 42 (P<0.001 for both). CD34+CD38- CSCs associated with MRD at day-15, increased BM blast cell count at diagnosis and at day-15 (P=0.015, P=0.005 and P=0.003). TIMP-1 overexpression associated with shorter DFS and OS rates (P=0.009 and P=0.048). Multivariate logistic regression analysis showed that both TIMP-1 [OR: 4.224, P=0.046], and CD34+CD38- CSCs [OR: 6.873, P=0.005] are independent diagnostic factors for pediatric ALL.Conclusion: TIMP-1 and CD34+CD38- CSCs could be useful independent diagnostic markers for pediatric ALL. Also, TIMP-1 is a promising prognostic marker for poor outcome of the patients.

Improving pneumococcal vaccination rates in pediatric acute lymphoblastic leukemia/lymphoblastic lymphoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18666-e18666
Author(s):  
Simone Chang ◽  
Alexandra Cheerva ◽  
Michael Angelo Huang ◽  
Kerry McGowan ◽  
Esther E Knapp ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Hematologic Malignancy ◽  
Lymphoblastic Leukemia ◽  
Pneumococcal Vaccination ◽  
Vaccination Rate ◽  
Lymphoblastic Lymphoma ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Vaccination Rates ◽  
Targeted Interventions ◽  
Pediatric All

e18666 Background: Pediatric Acute Lymphoblastic Leukemia/ Lymphoblastic Lymphoma (ALL/LLy) is the most common pediatric cancer. Invasive pneumococcal disease (IPD) is prevalent in this population and the Centers for Disease Control and Prevention recommends pneumococcal vaccination to decrease morbidity and mortality. Despite these recommendations, vaccination rates remain low and the incidence of IPD among children with hematologic malignancy is significantly higher compared to the average pediatric population. An interventional study was designed to improve the vaccination rate and reduce the incidence of IPD in our institution. Methods: A plan-do-study-act (PDSA) model of quality improvement (QI) was used. Chart review at our institute was done for the 6-month period of January 2020 - June 2020 and baseline rates for pneumococcal polysaccharide (PPSV23) vaccination were calculated. Patients were included if they were ≥ 2 years old, diagnosed with ALL/LLy, and undergoing maintenance. A multidisciplinary team performed the root cause analysis. Immunization records were obtained and reviewed and targeted interventions were implemented. The interventions used are outlined in Table. The percentage of pediatric ALL/LLy patients per month in maintenance who received age-appropriate pneumococcal vaccinations was monitored before and after the interventions. Results: Analysis of the 6-month retrospective cohort (n=36) showed a baseline vaccination rate of 5.5%. During the subsequent 6-month phase with interventions, 40 patients were prospectively enrolled. Demographics showed a mean age of 10.2 years (range, 2-21) and a predominantly male (66.7%) cohort. B-cell ALL/LLy comprised the majority (78.9%); the rest included T-cell ALL/LLy and mixed phenotype acute leukemia. As seen in Table, the percentage receiving at least 1 pneumococcal vaccine increased from 5.5% to 84.8% over the first 3 months, this plateaued around 81%. Completion of the series mirrored this and increased to 74.2%. Pre-visit planning and cues proved to be the most helpful interventions. Conclusions: Use of a PDSA model successfully improved pneumococcal vaccination rates in the pediatric ALL/LLy population. We suggest these results can be achieved with planning and implementation of the outlined interventions. [Table: see text]

scholarly journals Accumulation of high levels of methotrexate polyglutamates in lymphoblasts from children with hyperdiploid (greater than 50 chromosomes) B-lineage acute lymphoblastic leukemia: a Pediatric Oncology Group study

Blood ◽  
1992 ◽  
Vol 80 (5) ◽  
pp. 1316-1323 ◽  
Author(s):  
VM Whitehead ◽  
MJ Vuchich ◽  
SJ Lauer ◽  
D Mahoney ◽  
AJ Carroll ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Primary Component ◽  
Chromosome 9 ◽  
Dna Index ◽  
Free Survival ◽  
Continuation Therapy ◽  
Pediatric Oncology Group ◽  
B Lineage

Abstract Hyperdiploidy (greater than 50 chromosomes, or a DNA index greater than 1.16) confers a favorable prognosis in B-lineage acute lymphoblastic leukemia of childhood. Children with B-lineage acute lymphoblastic leukemia whose lymphoblasts at diagnosis accumulate high levels of methotrexate (MTX) and MTX polyglutamates (MTXPGs) in vitro experience a better event-free survival than those whose lymphoblasts do not (Blood 76:44, 1990). Lymphoblasts from 13 children with hyperdiploidy (greater than 50 chromosomes) accumulated high levels of MTX-PGs (1,095 and 571 to 2,346 pmol/10(9) cells [median and 25% to 75% intraquartile range]). These levels were higher than those in B-lineage lymphoblasts from 19 children with other aneuploidy (326 and 159 to 775 pmol/10(9) cells) and 15 children with diploidy (393 and 204 to 571 pmol/10(9) cells) (P = .0015). Chromosomal trisomies in hyperdiploid cases were highly nonrandom. Chromosome 9 was not one of the chromosomes involved in trisomies, even though this chromosome contains the gene for folate polyglutamate synthetase, which is the enzyme required for MTXPG synthesis. The correlation between MTXPG level and percentage of S- phase cells was weak, suggesting that increased levels of MTXPGs could not be attributed to elevated proportions of cells in active DNA synthesis. The ability of hyperdiploid lymphoblasts to accumulate high levels of MTXPGs may increase their sensitivity to MTX cytotoxicity, accounting in part for the improved outlook for hyperdiploid patients treated with regimens that emphasize MTX as a primary component of continuation therapy.

scholarly journals Methionine synthase A2756G polymorphism influences pediatric acute lymphoblastic leukemia risk: a meta-analysis

2019 ◽  
Vol 39 (1) ◽  
Author(s):  
Li-Min Ma ◽  
Hai-Ping Yang ◽  
Xue-Wen Yang ◽  
Lin-Hai Ruan
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Large Scale ◽  
Lymphoblastic Leukemia ◽  
Meta Analysis ◽  
Population Based ◽  
Methionine Synthase ◽  
China National Knowledge Infrastructure ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Pediatric All ◽  
And Control

Abstract Plenty of studies have investigated the effect of methionine synthase (MTR) A2756G polymorphism on risk of developing pediatric acute lymphoblastic leukemia (ALL), but the available results were inconsistent. Therefore, a meta-analysis was conducted to derive a more precise estimation of the association between MTR A2756G polymorphism and genetic susceptibility to pediatric ALL. The PubMed, Embase, Google Scholar, Web of Science, ScienceDirect, Wanfang Databases and China National Knowledge Infrastructure were systematically searched to identify all the previous published studies exploring the relationship between MTR A2756G polymorphism and pediatric ALL risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were applied to evaluate the strength of association. Sensitivity analysis and publication bias were also systematically assessed. This meta-analysis finally included ten available studies with 3224 ALL cases and 4077 matched controls. The results showed that there was significant association between MTR A2756G polymorphism and risk of pediatric ALL in overall population (AG vs. AA: OR = 1.13, 95%CI = 1.02–1.26, P = 0.02; AG+GG vs. AA: OR = 1.13, 95%CI = 1.02–1.25, P = 0.01; G allele vs. A allele: OR = 1.10, 95%CI = 1.01–1.20, P = 0.03). In the stratification analyses by ethnicity, quality score and control source, significant association was found in Caucasians, population-based designed studies and studies assigned as high quality. In conclusion, this meta-analysis suggests that MTR A2756G polymorphism may influence the development risk of pediatric ALL in Caucasians. Future large scale and well-designed studies are required to validate our findings.

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.

scholarly journals Opposing regulation of BIM and BCL2 controls glucocorticoid-induced apoptosis of pediatric acute lymphoblastic leukemia cells

Blood ◽  
2015 ◽  
Vol 125 (2) ◽  
pp. 273-283 ◽  
Author(s):  
Duohui Jing ◽  
Vivek A. Bhadri ◽  
Dominik Beck ◽  
Julie A. I. Thoms ◽  
Nurul A. Yakob ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Glucocorticoid Receptor ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cells ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Intronic Region ◽  
Key Points ◽  
Pediatric All ◽  
Induced Apoptosis

Key Points The glucocorticoid receptor coordinately regulates the antiapoptotic BCL2 and proapoptotic BIM genes in pediatric ALL cells in vivo. GR binding at a novel intronic region is associated with BIM transcription and dexamethasone sensitivity in pediatric ALL cells in vivo.

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