Evaluation of PAX5 gene in the early stages of leukemic B cells in the childhood B cell acute lymphoblastic leukemia

Fırtına, Sinem; Sayitoğlu, Müge; Hatırnaz, Özden; Erbilgin, Yücel; Oztunc, Ceren; Çınar, Sezgi; Yıldız, İnci; Çelkan, Tiraje; Anak, Sema; Ünüvar, Ayşegül; Devecioğlu, Ömer; Timur, Çetin; Aydoğan, Gönül; Akçay, Arzu; Atay, Didem; Türkkan, Emine; Karaman, Serap; Orhaner, Betül; Sarper, Nazan; Deniz, Günnur; Özbek, Uğur

doi:10.1016/j.leukres.2011.07.017

Cited by 12 publications

(10 citation statements)

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“…BSAP can result in increased or decreased gene expression and this can be regulated by additional proteins that BSAP is capable of interacting with via its protein-binding domain. BSAP overexpression generally confers proliferative phenotype in lymphoid malignancies especially B-ALL [ 24 , 25 ]. In light of this background, we explored the BSAP- Dleu2 regulation in mouse and human CLL cells.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic implications of activation of the host gene (Dleu2) promoter for miR-15a/16-1 in chronic lymphocytic leukemia

et al. 2013

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Genetic lesions and other regulatory events lead to silencing of the 13q14 locus in a majority of chronic lymphocytic leukemia (CLL) patients. This locus encodes a pair of critical pro-apoptotic microRNAs, miR-15a/16-1. Decreased levels of miR-15a/16-1 are critical for the increased survival exhibited by CLL cells. Similarly, in a de novo murine model of CLL, the NZB strain, germline-encoded regulation of the syntenic region resulted in decreased miR-15a/16-1. In this paper we have identified additional molecular mechanisms regulating miR-15a/16-1 levels and shown that the transcription factor BSAP (B cell Specific Activator Protein) directly interacts with Dleu2, the host gene containing the mir-15a/16-1 loci and via negative regulation of the Dleu2 promoter results in repression of mir-15a/16 expression. CLL patient B cell expression levels of BSAP were increased compared to control sources of B cells. With the use of siRNA mediated repression, the levels of BSAP were decreased in vitro in the NZB derived malignant B1 cell line, LNC, and in ex vivo CLL patient PBMC. BSAP knockdown led to an increase in the expression of miR-15a/16-1 and an increase in apoptosis and a cell cycle arrest in both the cell line and patient PBMC. Moreover, using Dleu2 promoter analysis by chromatin immunoprecipitation (ChIP) assay we have shown that BSAP directly interacts with the Dleu2 promoter. Derepression of the Dleu2 promoter via inhibition of histone deacetylation combined with BSAP knockdown increased miR-15a/16 expression and increased malignant B cell death. In summary, therapy targeting enhanced host gene Dleu2 transcription may augment CLL therapy.

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Section: Introductionmentioning

confidence: 99%

Therapeutic implications of activation of the host gene (Dleu2) promoter for miR-15a/16-1 in chronic lymphocytic leukemia

et al. 2013

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“…Pakistan lies in South East Asia having frequency of rs3780135 (47.1%) which is lower than previously reported in East Asian population. Firtina et al (2012) found polymorphism rs3780135 in B-ALL subjects with increased mRNA expression of PAX5 suggesting the possible role of SNP with increased proliferation of blast cells. In Pakistani population, minor allele frequency was significantly identified in B-ALL subjects (OR = 2.17, CI [1.37–3.43], P = 0.000).…”

Section: Discussionmentioning

confidence: 88%

Risk assessment of FLT3 and PAX5 variants in B-acute lymphoblastic leukemia: a case–control study in a Pakistani cohort

Khalid

Aslam

Ahmed

et al. 2019

PeerJ

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AIMS B-cell acute lymphoblastic leukemia (B-ALL) is amongst the most prevalent cancers of children in Pakistan. Genetic variations in FLT3 are associated with auto-phosphorylation of kinase domain that leads to increased proliferation of blast cells. Paired box family of transcription factor (PAX5) plays a critical role in commitment and differentiation of B-cells. Variations in PAX5 are associated with the risk of B-ALL. We aimed to analyze the association of FLT3 and PAX5 polymorphisms with B cell leukemia in Pakistani cohort. METHODS We collected 155 B-ALL subject and 155 control blood samples. For analysis, genotyping was done by tetra ARMS-PCR. SPSS was used to check the association of demographic factors of SNPs present in the population with the risk of B-ALL. RESULTS Risk allele frequency A at locus 13q12.2 (rs35958982, FLT3) was conspicuous and showed positive association (OR = 2.30, CI [1.20–4.50], P = 0.005) but genotype frequency (OR = 3.67, CI [0.75–18.10], P = 0.088) failed to show any association with the disease. At locus 9p13.2 (rs3780135, PAX5), the risk allele frequency was significantly higher in B-ALL subjects than ancestral allele frequency (OR = 2.17, CI [1.37–3.43], P = 0.000). Genotype frequency analysis of rs3780135 polymorphism exhibited the protective effect (OR = 0.55, CI [0.72–1.83], P = 0.029). At locus 13q12.2 (rs12430881, FLT3), the minor allele frequency G (OR = 1.15, CI [1.37–3.43], P = 0.043) and genotype frequency (OR = 2.52, P = 0.006) reached significance as showed p < 0.05. CONCLUSION In the present study, a strong risk of B-cell acute lymphoblastic leukemia was associated with rs35958982 and rs12430881 polymorphisms. However, rs3780135 polymorphism showed the protective effect. Additionally, other demographic factors like family history, smoking and consanguinity were also found to be important in risk assessment. We anticipate that the information from genetic variations in this study can aid in therapeutic approach in the future.

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“…Pakistan lies in South East Asia having frequency of rs3780135 (47.1%) which is lower than previously reported in East Asian population. Firtina et al, found polymorphism rs3780135 in B-ALL subjects with increased mRNA expression of PAX5 suggesting the possible role of SNP with increased proliferation of blast cells (Firtina et al, 2012). In Pakistani population, minor allele frequency was significantly identified in B-ALL subjects (OR=2.17, CI=1.37-3.43, P=0.000).…”

Section: Discussionmentioning

confidence: 98%

“…Heterozygous genotype GA (38.7%) was more frequently identified in our cohort than homozygous risk genotype AA (27.74%) which manifested significant difference in frequency (CI=0.72-1.83, P=0.029) and also showed protective effect (OR=0.55). PAX5 is involved in repression of T-cells, activation of Bcell proliferation from blast cell therefore, presence of any variant in this gene affects its pathway which may leads to increased expression of PAX5 and results into B-ALL (Firtina et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Peer Review #1 of "Risk assessment of FLT3 and PAX5 variants in B-acute lymphoblastic leukemia: a case–control study in a Pakistani cohort (v0.2)"

2019

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B-cell acute lymphoblastic leukemia (B-ALL) is amongst most prevalent cancers of children in Pakistan. Genetic variations in FLT3 are associated with auto-phosphorylation of kinase domain that leads to increased proliferation of blast cells. Paired box family of transcription factor (PAX5) plays a critical role in commitment and differentiation of B-cells. Variations in PAX5 are associated with the risk of BALL. We aimed to analyze the association of FLT3 and PAX5 polymorphisms with B cell leukemia in Pakistani cohort. METHODS: We collected 155 BALL subject and 155 control blood samples. For analysis, genotyping was done by tetra ARMS-PCR. SPSS was used to check the association of demographic factors of SNPs present in the population with the risk of BALL. RESULTS: Risk allele frequency A at locus 13q12.2 (rs35958982, FLT3) was conspicuous and showed positive association (OR= 2.30, CI=1.20-4.50, P=0.005) but genotype frequency (OR=3.67, CI=0.75-18.10, P=0.088) failed to show any association with the disease. At locus 9p13.2 (rs3780135, PAX5), the risk allele frequency was significantly more in BALL subjects than ancestral allele frequency (OR=2.17, CI=1.37-3.43, P=0.000). Genotype frequency analysis of rs3780135 polymorphism exhibited the protective effect (OR=0.55, CI=0.72-1.83, P=0.029). At locus 13q12.2 (rs12430881, FLT3), the minor allele frequency G (OR=1.15, CI=1.37-3.43, P=0.043) and genotype frequency (OR=2.52, P=0.006) reached significance as showed p<0.05. CONCLUSION: In present study, a strong risk of B-cell acute lymphoblastic leukemia was associated with rs35958982 and rs12430881 polymorphisms. However, rs3780135 polymorphism showed the protective effect. Additionally, other demographic factors like family history, smoking and consanguinity were also found to be important in risk assessment. We anticipate that the information from genetic variations in this study can aid in therapeutic approach in the future.

show abstract

Evaluation of PAX5 gene in the early stages of leukemic B cells in the childhood B cell acute lymphoblastic leukemia

Cited by 12 publications

References 31 publications

Therapeutic implications of activation of the host gene (Dleu2) promoter for miR-15a/16-1 in chronic lymphocytic leukemia

Therapeutic implications of activation of the host gene (Dleu2) promoter for miR-15a/16-1 in chronic lymphocytic leukemia

Risk assessment of FLT3 and PAX5 variants in B-acute lymphoblastic leukemia: a case–control study in a Pakistani cohort

Peer Review #1 of "Risk assessment of FLT3 and PAX5 variants in B-acute lymphoblastic leukemia: a case–control study in a Pakistani cohort (v0.2)"

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