Differential Response Of Leukemic Blasts To Dexamethasone and Prednisone Occurs At Sub-Saturating Doses

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4915-4915
Author(s):  
Miles A. Pufall ◽  
Hongxing Yang ◽  
Dawne N. Shelton
Keyword(s):  
Gene Expression ◽  
Cell Lines ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Cell Type ◽  
Cell Precursor ◽  
Expression Of Genes ◽  
The Difference ◽  
Genomic Response ◽  
Differential Expression Of Genes

Abstract Dexamethasone (dex) and prednisone (pred) are highly related glucocorticoids that are used in the treatment of leukemias and lymphomas. Recently it was shown that dex produces better outcomes in children with high-risk B cell precursor acute lymphoblastic leukemia than pred. Although this result was consistent with the accepted potencies of the two drugs, the reason for this difference is not well understood. Glucocorticoids work primarily by binding and activating the glucocorticoid receptor, which, when bound, associates with genomic response elements to orchestrate gene expression programs. We hypothesized that dex regulates key genes that drive apoptosis in BCP-ALL more strongly. To test this we used microarrays to measure the differential expression of genes in response to saturating doses of dex and pred in three cell lines. Dex and pred induced very similar patterns of gene expression in each cell type, with an overlap of about 60%. Surprisingly, when we compared the 40% of genes that were regulated by dex or pred alone in each cell line, there were no commonly regulated genes among all cell lines. Further, for the 150 genes commonly regulated by both dex and pred in all three cell lines, there were no differences in the magnitude of response, suggested that the difference might lie at a lower, more functional doses. We tested this using RNA sequencing at five concentrations of both dex and pred in a primary patient sample. Consistent with their potency, the average regulated gene required eight times more pred than dex. Interestingly, when we performed unsupervised clustering of regulated genes by concentration, we found more modest differences in the concentration required for the onset of regulation, and that pred selectively suppressed expression of a block of genes at lower concentrations. These data suggest that rather than specific genes being regulated by dex, or simply a more potent response of the same genes, that the difference in apoptosis induction may be due to surprisingly different responses at sub-saturating concentrations. Disclosures: No relevant conflicts of interest to declare.

Characterization of lincRNA BALIR-6 in MLL rearranged B-lymphoblastic leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3730-3730
Author(s):  
Norma Iris Rodriguez-Malave ◽  
Weihong Yan ◽  
Giuseppe Basso ◽  
Martina Pigazzi ◽  
Dinesh S. Rao
Keyword(s):  
Gene Expression ◽  
B Cells ◽  
B Cell ◽  
Cell Lines ◽  
Microarray Data ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Regulate Gene Expression ◽  
In Cis ◽  
Regulate Gene

Abstract A new class of non-coding RNA, known as long intergenic non-coding RNAs (lincRNAs), has only recently been described. These lincRNAs have been found to play a role in various molecular processes within the cell including gene regulation, acting as sinks for microRNAs, and regulating splicing, implicating them in development and oncogenic processes. B lymphoblastic leukemia (B acute lymphoblastic leukemia; B-ALL), a malignancy of precursor B-cells, harbors mutations and translocations that result in a dysregulated gene expression. Interestingly, dysregulated expression of lincRNAs has been found in various cancers, but has not yet been described in B-ALL. Recently, we completed a gene expression profiling study in human B-ALL samples, which showed differential lincRNA expression in samples with particular cytogenetic abnormalities. This led us to hypothesize that lincRNAs may be related to disease pathogenesis. Here, we describe a promising lincRNA from our microarray data designated B-ALL associated long intergenic RNA 6 (BALIR-6). Expression of BALIR-6 is highest in patient samples carrying the MLL rearrangement (n=16; when compared to patients with TEL-AML1-translocated, n=39; E2A-PBX1-translocated, n=8; BCR-ABL-translocated, n=3; and cytogenetically normal cases, n=56; 1-way ANOVA p<0.0001) and showed significant variance in the expression level based on the immunophenotype (1-way ANOVA p=0.0004). BALIR-6 is located on chromosome 3p24.3 in humans, and exists in a syntenic gene block in with neighboring genes SATB1 and TBC1D5, and is conserved in mammals. Rapid Amplification of cDNA Ends (RACE) uncovered multiple transcript isoforms; from these, three were cloned out and sequenced, corresponding to the genomic locus as predicted. In B-ALL cell lines, BALIR-6 expression was highest in RS411 cells, which carry the MLL rearrangement, when compared to other B-ALL cell lines. This suggests that the cell lines may show a similar expression pattern to human B-ALL samples. To study the functional role of BALIR-6 we utilized siRNA in a mmu-miR-155 expression cassette to knockdown the transcript. In RS411 cells we observed a reduction in proliferation by MTS assay. Additionally, we observed an increase Sub-G0 cells and a decrease in G2-M phase cells by propidium iodide staining, suggesting an increase in apoptosis. Conversely, overexpression of BALIR-6 in a mouse pre-B cell line (70Z/3), leads to an increase in proliferation. Interestingly, during normal B cell development, BALIR-6 is dynamically expressed, with high expression in pre-B cells and subsequent downregulation, suggesting that a normal role during development is being hijacked in patients with B-ALL. Mechanistically, a few recent studies have described that lincRNAs can regulate gene expression in cis. To explore whether BALIR 6 regulates surrounding genes in cis, we analyzed microarray data of MLL rearranged B-ALL samples, finding that expression of BALIR-6 correlates with expression of surrounding genes SATB1 and TBC1D5. Interestingly for SATB1, this correlation is also seen in human B cell developmental stages. Altering BALIR-6 expression by siRNA mediated knockdown or overexpression causes an effect on the expression of surrounding genes SATB1 and TBC1D5. Previous findings have shown that dysregulated SATB1 has been seen in a variety of malignancies, suggesting a mechanism for how BALIR-6 may produce the changes in cell growth and apoptosis described above. Altogether, these results identify a novel and interesting RNA transcript with the potential to regulate gene expression and pathogenesis in B-ALL with MLL rearrangement, suggesting novel diagnostic, prognostic, and therapeutic implications. Disclosures: No relevant conflicts of interest to declare.

Value of EVI1 Gene Expression Level in Adult Acute Lymphoblastic Leukemia (ALL): A Study from the Group for Research on Adult ALL (GRAALL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1081-1081
Author(s):  
Claire Abbal ◽  
Raouf Ben Abdelali ◽  
Marina Lafage ◽  
Françoise Huguet ◽  
Thibaut Leguay ◽  
...  
Keyword(s):  
Gene Expression ◽  
Patient Outcome ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Expression Level ◽  
Prognostic Impact ◽  
Complex Karyotype ◽  
Cell Precursor ◽  
Genetic Profiles ◽  
Lower Expression

Abstract Background: EVI1 gene overexpression is found in approximately 10% of acute myeloid leukemia (AML) patients, with a higher frequency seen in AML carrying chromosome 3q26 abnormality or MLL gene rearrangement, and associated with a dismal prognosis. Deregulation of EVI1 expression has also been reported in ALL, but its prognostic impact is unclear. Here, we retrospectively analyzed EVI1 expression in a large cohort of adult ALL patients, its correlation with ALL subsets, and its impact on patient outcome. Patients and Methods: EVI1 gene expression was measured by RQ-PCR detecting all splicing variants, with PBGD as control gene. We used dilutions of EVI1+ SKOV3 (kindly provided by Peter Valk, Rotterdam, The Netherlands) and EVI1-neg HL-60 cell line cDNA to build EVI1 and PBGD standard curves. Results were expressed as EVI1/PBGD ratio x 100. Blast samples from 354 patients treated in the GRAALL-2003/2005 and GRAAPH-2005 trials (191 B-cell precursor [BCP]-ALL, including 138 Ph-neg and 53 Ph+; 163 T-ALL) and 62 controls were analyzed. Immunophenotype results were centrally reviewed. In controls, median EVI1 expression level was 0.33% (Q1-Q3, 0.20-0.69). For prognostic analysis, we used the 1st and 99th percentiles of the controls (0.05% and 1.65%) to define patients with low and high EVI1 expression, respectively. Clinical endpoints were cumulative incidence of failure (CIF, failure meaning primary refractoriness or relapse) and event-free survival (EFS). Results: As illustrated in Figure 1, we observed that, as in one AML series, EVI1 expression may be up or down regulated in adult ALL. When compared to controls, the proportions of low and high EVI1 patients were 21 and 23% in Ph-neg BCP-ALL, 9 and 42% in Ph+ ALL, and 21 and 18% in T-ALL, respectively. In BCP-ALL patients, median EVI1 expression was similar to controls (0.53%; Q1-Q3, 0.11-1.88; p=0.15), but higher in the Ph+ as compared to the Ph-neg subgroup (0.93% versus 0.36%; p<0.001). In T-ALL patients, median expression tended to be lower than in controls (0.22%; Q1-Q3, 0.06-0.85; p=0.058). In these three ALL subgroups, EVI1 expression did not correlate with age or WBC. Among Ph-neg BCP-ALL patients, a lower expression was found in MLL-AF4+ t(4;11) cases (median, 0.04%; p<0.001), while no differences were observed for cases with t(1;19), an14q32, low hypodiploidy/near triploidy, complex karyotype, or IKZF1 deletion. Among T-ALL patients, a lower expression was found in cases with complex karyotype (median, 0.05%; p=0.03), while no differences were observed for cases with TLX1 overexpression, NOTCH1/FBXW7 mutation, N/K-RAS mutation or PTEN alteration. Only one patient had 3q26 abnormality (T-ALL with high EVI1 expression). Low or high EVI1 expression had no prognostic impact in Ph-neg as well as Ph+ BCP-ALL patients. In T-ALL, the proportion of patients with low EVI1 expression was more frequent in early and mature than in cortical T-ALL (33% and 33% vs 11%; p=0.002 and 0.028, respectively) and associated with a higher CIF (HR, 2.03; p=0.017) and shorter EFS (HR, 1.59; p=0.072). Low EVI1 expression was also significantly associated with an early T-cell precursor (ETP) phenotype (37.5% vs 18%; p=0.028). After adjustment on cortical and ETP phenotypes, as well as on 4-gene (NOTCH1/FBXW7/RAS/PTEN) genetic profiles, low EVI1 expression and high-risk genetic profiles remained independently associated with higher CIF (p=0.015 and <0.001, respectively) and shorter EFS (p=0.045 and 0.002, respectively). Conclusion: Overall, these results confirm that EVI1 gene expression is frequently deregulated in adult ALL. In BCP-ALL, down-regulation is observed in t(4;11) and up-regulation in BCR-ABL cases. Further studies are needed to confirm that, in T-ALL, a lower expression is associated with the early, mature and ETP phenotypes and independently predictive of a worse patient outcome. Figure 1 Figure 1. EVI1 gene expression in ALL and control samples. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Role of SMAD7 Downstream of TEL-AML1 Signalling in t(12;21) Acute Lymphoblastic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4823-4823 ◽  
Author(s):  
Aishwarya Sundaresh ◽  
Maurizio Mangolini ◽  
Jasper de Boer ◽  
Mike Hubank ◽  
Nicholas Goulden ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Lines ◽  
Conflicts Of Interest ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Xenograft Model ◽  
Direct Role ◽  
Hematopoietic Stem ◽  
Childhood All

Abstract The single most frequent chromosomal translocation associated with childhood ALL is the t(12;21) rearrangement that creates a fusion gene between TEL (ETV6) and AML1 (RUNX1). Although TEL-AML1+ patients have very good prognoses, relapses occur in up to 20% of patients and many patients face long-term side effects of chemotherapy. Recent data has shown that TEL-AML1 has a direct role in inducing signal transducer and activator of transcription 3 (STAT3) activation in human t(12;21) leukemia. This activation has been shown to transcriptionally induce MYC and is critical for survival of TEL-AML+ leukemia cells. Here, we demonstrate that STAT3 also regulates SMAD7 gene expression. SMAD7 is an antagonist of TGF-β signaling, functioning through a negative feedback mechanism, but is also known to function in other biological pathways. Interestingly, SMAD7 has also been shown to play a role in promoting self-renewal of hematopoietic stem cells. We show that both pharmacological and mechanistic inhibition of STAT3 results in down regulation of SMAD7 gene expression in TEL-AML1+ cell lines. This result was specific to TEL-AML1+ cells and not found in cells of other ALL subtypes. To understand the role played by SMAD7 in TEL-AML1+ cells, we used lentiviral vectors expressing shRNA targeting SMAD7. Interestingly, SMAD7 silencing was found to inhibit proliferation of TEL-AML1+ cell lines, eventually leading to growth arrest and apoptosis. Furthermore, we have established that this effect is not mediated through TGF-β signalling. This poster highlights the results of RNA-seq performed on TEL-AML1+ cells with SMAD7 knockdown and in vivo xenograft model of SMAD7 shRNA in TEL-AML+ ALL. Disclosures No relevant conflicts of interest to declare.

Genome-Wide Analysis Reveals Conserved and Divergent Features of Notch1/RBPJ Binding in Human and Murine T Lymphoblastic Leukemia Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5236-5236
Author(s):  
Jon C Aster ◽  
Hongfang Wang ◽  
James Zou ◽  
Yumi Yashiro-Ohtani ◽  
Bo Zhao ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Cell Lines ◽  
Binding Sites ◽  
Target Genes ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Human T Cell ◽  
Two Factors

Abstract Abstract 5236 Activated Notch1 regulates gene expression by associating with the DNA-binding factor RBPJ and is an important oncoprotein in murine and human T cell acute lymphoblastic leukemia/lymphoma (T-ALL), yet the interplay between Notch1 and other factors that regulate the transcriptional output of T-ALL cells is poorly understood. Using ChIP-Seq and starting with Notch1-dependent human and murine T-ALL cell lines, we find that Notch1 binds preferentially to promoters, to RBPJ binding sites, and near sites for ZNF143, as well as Ets and Runx factors. By ChIP-Seq, ZNF143 binds to ∼40% of Notch1 sites, whereas Ets1 binding is observed within 100 basepairs of ∼70% of genomic Notch1 binding sites. Notch1/ZNF143 “co-sites” have high Notch1 and ZNF143 signals, frequent co-binding of RBPJ to sites embedded within ZNF143 motifs, strong promoter bias, and low mean levels of “activated” chromatin marks. RBPJ and ZNF143 binding to DNA is mutually exclusive in vitro, suggesting RBPJ/Notch1 and ZNF143 complexes exchange on these sites in T-ALL cell lines. In contrast, Ets1 binding sites flank RBPJ/Notch1 binding sites and are associated with high levels of activated chromatin marks, whereas Runx sites are predominantly intergenic. Although Notch1 predominantly binds promoters, ∼75% of direct Notch1 target genes lack promoter binding and appear to be regulated by enhancers, which were identified near MYC, DTX1, IGF1R, IL7R and the GIMAP gene cluster. Both Ets1 and Notch1 binding to an intronic enhancer located in DTX1 were required for expression of this well characterized Notch1 target gene, suggesting that these two factors coordinately regulate DTX1 expression. Although the association of Notch1 binding with ZNF143, Ets, and Runx sites was highly conserved, binding near certain important genes showed substantial divergence. For example, in human T-ALL lines Notch1/RBPJ bind a 3' enhancer near the IL7R gene, whereas in murine T-ALL lines no binding was observed near Il7r. Similarly, in human T-ALL lines Notch1/RBPJ bound an enhancer located ∼565 kb 5' of MYC, whereas in murine T-ALL cells Notch1/RBPJ bound an enhancer located ∼1 Mb 3' of Myc. Human and murine T-ALL genomes also have many sites that bind only RBPJ. Murine RBPJ “only” sites are highly enriched for imputed sites for the corepressor REST, whereas human RPBJ “only” sites lack REST motifs and are more highly enriched for imputed CREB binding sites. Thus, there is a conserved network of cis-regulatory factors that interacts with Notch1 to regulate gene expression in T-ALL cell lines, as well as novel classes of divergent RBPJ “only” sites that also likely regulate transcription. To extend these findings to normal and pathophysiologic tissues, ChIP-Seq was used to identify RBPJ/Notch1 binding sites in primary murine thymocytes and primary murine T-ALL associated with Notch1 gain-of-function mutations. Early findings appear to indicate that primary T-ALLs closely resemble normal DN3a thymocytes in terms of the distribution of Notch1 binding sites and associated chromatin marks. These data suggest that Notch1-driven T-ALLs epigenetically resemble the DN3a stage of T cell development, during which Notch1 signaling is high and cells are rapidly proliferating. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Association of relapse-linked ARID5B single nucleotide polymorphisms with drug resistance in B-cell precursor acute lymphoblastic leukemia cell lines

2020 ◽  
Author(s):  
MINORI TAMAI ◽  
Meixian Huang ◽  
Keiko Kagami ◽  
Masako Abe ◽  
Tamao Shinohara ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
Cell Lines ◽  
Risk Allele ◽  
Lymphoblastic Leukemia ◽  
Chemotherapeutic Agents ◽  
Nucleotide Polymorphisms ◽  
Cell Precursor ◽  
Single Nucleotide ◽  
Ic50 Values

Abstract Background The genetic variants of the ARID5B gene have recently been reported to be associated with disease susceptibility and treatment outcome in childhood acute lymphoblastic leukemia (ALL). However, few studies have explored the association of ARID5B with sensitivities to chemotherapeutic agents. Methods We genotyped susceptibility-linked rs7923074 and rs10821936 as well as relapse-linked rs4948488, rs2893881, and rs6479778 of ARDI5B by direct sequencing of polymerase chain reaction (PCR) products in 72 B-cell precursor-ALL (BCP-ALL) cell lines established from Japanese patients. We also quantified their ARID5B expression levels by real-time reverse transcription PCR, and determined their 50% inhibitory concentration (IC50) values by alamarBlue assays in nine representative chemotherapeutic agents used for ALL treatment. Results No significant associations were observed in genotypes of the susceptibility-linked single nucleotide polymorphisms (SNPs) and the relapsed-linked SNPs with ARID5B gene expression levels. Of note, IC50 values of vincristine (VCR) (median IC50: 39.6 ng/ml) in 12 cell lines with homozygous genotype of risk allele (C) in the relapse-linked rs4948488 were significantly higher (p=0.031 in Mann–Whitney U test) than those (1.04 ng/ml) in 60 cell lines with heterozygous or homozygous genotypes of the non-risk allele (T). Furthermore, the IC50 values of mafosfamide [Maf; active metabolite of cyclophosphamide (CY)] and cytarabine (AraC) tended to be associated with the genotype of rs4948488. Similar associations were observed in genotypes of the relapse-linked rs2893881 and rs6479778, but not in those of the susceptibility-linked rs7923074 and rs10821936. In addition, the IC50 values of methotrexate (MTX) were significantly higher (p=0.023) in 36 cell lines with lower ARID5B gene expression (median IC50: 37.1 ng/ml) than those in the other 36 cell lines with higher expression (16.9 ng/ml). Conclusion These observations in 72 BCP-ALL cell lines suggested that the risk allele of the relapse-linked SNPs of ARID5B may be involved in a higher relapse rate because of resistance to chemotherapeutic agents such as VCR, CY, and AraC. In addition, lower ARID5B gene expression may be associated with MTX resistance.

scholarly journals Association of relapse-linked ARID5B single nucleotide polymorphisms with drug resistance in B-cell precursor acute lymphoblastic leukemia cell lines

2020 ◽  
Author(s):  
MINORI TAMAI ◽  
Meixian Huang ◽  
Keiko Kagami ◽  
Masako Abe ◽  
Shinpei Somazu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
Cell Lines ◽  
Risk Allele ◽  
Lymphoblastic Leukemia ◽  
Chemotherapeutic Agents ◽  
Nucleotide Polymorphisms ◽  
Cell Precursor ◽  
Single Nucleotide ◽  
Ic50 Values

Abstract Background The genetic variants of the ARID5B gene have recently been reported to be associated with disease susceptibility and treatment outcome in childhood acute lymphoblastic leukemia (ALL). However, few studies have explored the association of ARID5B with sensitivities to chemotherapeutic agents. Methods We genotyped susceptibility-linked rs7923074 and rs10821936 as well as relapse-linked rs4948488, rs2893881, and rs6479778 of ARDI5B by direct sequencing of polymerase chain reaction (PCR) products in 72 B-cell precursor-ALL (BCP-ALL) cell lines established from Japanese patients. We also quantified their ARID5B expression levels by real-time reverse transcription PCR, and determined their 50% inhibitory concentration (IC50) values by alamarBlue assays in nine representative chemotherapeutic agents used for ALL treatment. Results No significant associations were observed in genotypes of the susceptibility-linked single nucleotide polymorphisms (SNPs) and the relapsed-linked SNPs with ARID5B gene expression levels. Of note, IC50 values of vincristine (VCR) (median IC50: 39.6 ng/ml) in 12 cell lines with homozygous genotype of risk allele (C) in the relapse-linked rs4948488 were significantly higher (p=0.031 in Mann–Whitney U test) than those (1.04 ng/ml) in 60 cell lines with heterozygous or homozygous genotypes of the non-risk allele (T). Furthermore, the IC50 values of mafosfamide [Maf; active metabolite of cyclophosphamide (CY)] and cytarabine (AraC) tended to be associated with the genotype of rs4948488. Similar associations were observed in genotypes of the relapse-linked rs2893881 and rs6479778, but not in those of the susceptibility-linked rs7923074 and rs10821936. In addition, the IC50 values of methotrexate (MTX) were significantly higher (p=0.023) in 36 cell lines with lower ARID5B gene expression (median IC50: 37.1 ng/ml) than those in the other 36 cell lines with higher expression (16.9 ng/ml). Conclusion These observations in 72 BCP-ALL cell lines suggested that the risk allele of the relapse-linked SNPs of ARID5B may be involved in a higher relapse rate because of resistance to chemotherapeutic agents such as VCR, CY, and AraC. In addition, lower ARID5B gene expression may be associated with MTX resistance.

scholarly journals Association of relapse-linked ARID5B single nucleotide polymorphisms with drug resistance in B-cell precursor acute lymphoblastic leukemia cell lines

2020 ◽  
Author(s):  
MINORI TAMAI ◽  
Meixian Huang ◽  
Keiko Kagami ◽  
Masako Abe ◽  
Shinpei Somazu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
Cell Lines ◽  
Risk Allele ◽  
Lymphoblastic Leukemia ◽  
Chemotherapeutic Agents ◽  
Nucleotide Polymorphisms ◽  
Cell Precursor ◽  
Single Nucleotide ◽  
Ic50 Values

Abstract Background The genetic variants of the ARID5B gene have recently been reported to be associated with disease susceptibility and treatment outcome in childhood acute lymphoblastic leukemia (ALL). However, few studies have explored the association of ARID5B with sensitivities to chemotherapeutic agents. Methods We genotyped susceptibility-linked rs7923074 and rs10821936 as well as relapse-linked rs4948488, rs2893881, and rs6479778 of ARDI5B by direct sequencing of polymerase chain reaction (PCR) products in 72 B-cell precursor-ALL (BCP-ALL) cell lines established from Japanese patients. We also quantified their ARID5B expression levels by real-time reverse transcription PCR, and determined their 50% inhibitory concentration (IC50) values by alamarBlue assays in nine representative chemotherapeutic agents used for ALL treatment. Results No significant associations were observed in genotypes of the susceptibility-linked single nucleotide polymorphisms (SNPs) and the relapsed-linked SNPs with ARID5B gene expression levels. Of note, IC50 values of vincristine (VCR) (median IC50: 39.6 ng/ml) in 12 cell lines with homozygous genotype of risk allele (C) in the relapse-linked rs4948488 were significantly higher (p=0.031 in Mann–Whitney U test) than those (1.04 ng/ml) in 60 cell lines with heterozygous or homozygous genotypes of the non-risk allele (T). Furthermore, the IC50 values of mafosfamide [Maf; active metabolite of cyclophosphamide (CY)] and cytarabine (AraC) tended to be associated with the genotype of rs4948488. Similar associations were observed in genotypes of the relapse-linked rs2893881 and rs6479778, but not in those of the susceptibility-linked rs7923074 and rs10821936. In addition, the IC50 values of methotrexate (MTX) were significantly higher (p=0.023) in 36 cell lines with lower ARID5B gene expression (median IC50: 37.1 ng/ml) than those in the other 36 cell lines with higher expression (16.9 ng/ml). Conclusion These observations in 72 BCP-ALL cell lines suggested that the risk allele of the relapse-linked SNPs of ARID5B may be involved in a higher relapse rate because of resistance to chemotherapeutic agents such as VCR, CY, and AraC. In addition, lower ARID5B gene expression may be associated with MTX resistance.

Chemo-sensitivity in a panel of B-cell precursor acute lymphoblastic leukemia cell lines, YCUB series, derived from children

2009 ◽  
Vol 33 (10) ◽  
pp. 1386-1391 ◽  
Author(s):  
Hiroaki Goto ◽  
Takuya Naruto ◽  
Reo Tanoshima ◽  
Hiromi Kato ◽  
Tomoko Yokosuka ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Cell Precursor ◽  
Leukemia Cell Lines
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