BACH2 AND BCL6 COOPERATIVELY FUNCTION AS TUMOUR SUPPRESSORS IN CLL
(Abstract release date: 05/19/16)
EHA Library. Eswaran J. 06/09/16; 132626; E1077
Dr. Jeyanthy Eswaran
Contributions
Contributions
Abstract
Abstract: E1077
Type: Eposter Presentation
Background
Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the Western World. Aberrant germinal center (GC) reactions could be a triggering factor in CLL, potentially contributing to its pathogenesis. The transcriptional repressors BCL6 (B-Cell CLL/Lymphoma 6) and BACH2 (BTB and CNC Homology 1, Basic Leucine Zipper Transcription Factor 2) are crucial regulators of GC B-cell fate. The double heterozygous Bcl6-/+ Bach2-/+ mice exhibit profound reduction in GC formation in response to T-cell dependent antigen immunization. In GC B cells, the stability of BACH2 protein is regulated by BCL6 and 30% of BACH2 DNA binding sites overlap with BCL6 binding sites. Both proteins are upregulated and interaction between BACH2 and BCL6 represses transcription of PRDM1 (PR Domain Containing 1, With ZNF Domain), a key driver of plasma cell differentiation.
Aims
The aim of the study is to determine the role of these two critical GC B-cells regulators, BCL6 and BACH2 in CLL and investigate whether there is a functional collaboration between them in CLL using a patient sample cohort comprising 102 patients.
Methods
We have analyzed 102 CLL samples using TaqMan quantitative real-time PCR (qPCR) and calculated the relative expression by the 2–ΔΔCt method. A ROC curve was generated to identify the optimal diagnostic cut-off. The expression was then split at this cut-off and the resulting dichotomous variable was included in a survival analysis.
Results
We observed different levels of BCL6 and BACH2 expression throughout the CLL cases analysed. Median RQ (Relative Quantity) was 32.47 (range 4.04-153.29) for BCL6 and 232.62 (range 16.50-1132.30) for BACH2. Interestingly, CLL cases expressing low levels of BCL6 and BACH2 mRNA had significantly shorter overall survival (OS) than high BCL6 and BACH2-expressing samples. Moreover, the low expression of BACH2 and BCL6 specifically decreased OS of CLL patients with mutated IgVH and 11q and 13q deletions. BACH2 mRNA expression negatively correlates to the expression of CD38 (Pearson Correlation coefficient = -.418, p=.011), a poor prognostic factor in CLL. Finally, we identified a positive correlation between BCL6 and BACH2 expression (Pearson correlation coefficient = .335, p=.001), suggesting that these two factors could act synergistically in CLL. We also assessed the impact of BACH2 expression in combination with other variables that are known to be relevant for CLL prognosis (age and 17p deletion) and we identified a prognostic index (PI = 2.6). According to this model, patients with a PI <= 2.6 have a shorter OS compared to patients with a PI > 2.6 (p = 0.004).
Conclusion
Taken together, our study shows the prognostic role of BCL6 and BACH2 in CLL and the possibility of increased B cell receptor signalling due to the lack of Bcl6 and BACH2.
Session topic: E-poster
Keyword(s): B cell chronic lymphocytic leukemia, BCL6
Type: Eposter Presentation
Background
Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the Western World. Aberrant germinal center (GC) reactions could be a triggering factor in CLL, potentially contributing to its pathogenesis. The transcriptional repressors BCL6 (B-Cell CLL/Lymphoma 6) and BACH2 (BTB and CNC Homology 1, Basic Leucine Zipper Transcription Factor 2) are crucial regulators of GC B-cell fate. The double heterozygous Bcl6-/+ Bach2-/+ mice exhibit profound reduction in GC formation in response to T-cell dependent antigen immunization. In GC B cells, the stability of BACH2 protein is regulated by BCL6 and 30% of BACH2 DNA binding sites overlap with BCL6 binding sites. Both proteins are upregulated and interaction between BACH2 and BCL6 represses transcription of PRDM1 (PR Domain Containing 1, With ZNF Domain), a key driver of plasma cell differentiation.
Aims
The aim of the study is to determine the role of these two critical GC B-cells regulators, BCL6 and BACH2 in CLL and investigate whether there is a functional collaboration between them in CLL using a patient sample cohort comprising 102 patients.
Methods
We have analyzed 102 CLL samples using TaqMan quantitative real-time PCR (qPCR) and calculated the relative expression by the 2–ΔΔCt method. A ROC curve was generated to identify the optimal diagnostic cut-off. The expression was then split at this cut-off and the resulting dichotomous variable was included in a survival analysis.
Results
We observed different levels of BCL6 and BACH2 expression throughout the CLL cases analysed. Median RQ (Relative Quantity) was 32.47 (range 4.04-153.29) for BCL6 and 232.62 (range 16.50-1132.30) for BACH2. Interestingly, CLL cases expressing low levels of BCL6 and BACH2 mRNA had significantly shorter overall survival (OS) than high BCL6 and BACH2-expressing samples. Moreover, the low expression of BACH2 and BCL6 specifically decreased OS of CLL patients with mutated IgVH and 11q and 13q deletions. BACH2 mRNA expression negatively correlates to the expression of CD38 (Pearson Correlation coefficient = -.418, p=.011), a poor prognostic factor in CLL. Finally, we identified a positive correlation between BCL6 and BACH2 expression (Pearson correlation coefficient = .335, p=.001), suggesting that these two factors could act synergistically in CLL. We also assessed the impact of BACH2 expression in combination with other variables that are known to be relevant for CLL prognosis (age and 17p deletion) and we identified a prognostic index (PI = 2.6). According to this model, patients with a PI <= 2.6 have a shorter OS compared to patients with a PI > 2.6 (p = 0.004).
Conclusion
Taken together, our study shows the prognostic role of BCL6 and BACH2 in CLL and the possibility of increased B cell receptor signalling due to the lack of Bcl6 and BACH2.
Session topic: E-poster
Keyword(s): B cell chronic lymphocytic leukemia, BCL6
Abstract: E1077
Type: Eposter Presentation
Background
Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the Western World. Aberrant germinal center (GC) reactions could be a triggering factor in CLL, potentially contributing to its pathogenesis. The transcriptional repressors BCL6 (B-Cell CLL/Lymphoma 6) and BACH2 (BTB and CNC Homology 1, Basic Leucine Zipper Transcription Factor 2) are crucial regulators of GC B-cell fate. The double heterozygous Bcl6-/+ Bach2-/+ mice exhibit profound reduction in GC formation in response to T-cell dependent antigen immunization. In GC B cells, the stability of BACH2 protein is regulated by BCL6 and 30% of BACH2 DNA binding sites overlap with BCL6 binding sites. Both proteins are upregulated and interaction between BACH2 and BCL6 represses transcription of PRDM1 (PR Domain Containing 1, With ZNF Domain), a key driver of plasma cell differentiation.
Aims
The aim of the study is to determine the role of these two critical GC B-cells regulators, BCL6 and BACH2 in CLL and investigate whether there is a functional collaboration between them in CLL using a patient sample cohort comprising 102 patients.
Methods
We have analyzed 102 CLL samples using TaqMan quantitative real-time PCR (qPCR) and calculated the relative expression by the 2–ΔΔCt method. A ROC curve was generated to identify the optimal diagnostic cut-off. The expression was then split at this cut-off and the resulting dichotomous variable was included in a survival analysis.
Results
We observed different levels of BCL6 and BACH2 expression throughout the CLL cases analysed. Median RQ (Relative Quantity) was 32.47 (range 4.04-153.29) for BCL6 and 232.62 (range 16.50-1132.30) for BACH2. Interestingly, CLL cases expressing low levels of BCL6 and BACH2 mRNA had significantly shorter overall survival (OS) than high BCL6 and BACH2-expressing samples. Moreover, the low expression of BACH2 and BCL6 specifically decreased OS of CLL patients with mutated IgVH and 11q and 13q deletions. BACH2 mRNA expression negatively correlates to the expression of CD38 (Pearson Correlation coefficient = -.418, p=.011), a poor prognostic factor in CLL. Finally, we identified a positive correlation between BCL6 and BACH2 expression (Pearson correlation coefficient = .335, p=.001), suggesting that these two factors could act synergistically in CLL. We also assessed the impact of BACH2 expression in combination with other variables that are known to be relevant for CLL prognosis (age and 17p deletion) and we identified a prognostic index (PI = 2.6). According to this model, patients with a PI <= 2.6 have a shorter OS compared to patients with a PI > 2.6 (p = 0.004).
Conclusion
Taken together, our study shows the prognostic role of BCL6 and BACH2 in CLL and the possibility of increased B cell receptor signalling due to the lack of Bcl6 and BACH2.
Session topic: E-poster
Keyword(s): B cell chronic lymphocytic leukemia, BCL6
Type: Eposter Presentation
Background
Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in the Western World. Aberrant germinal center (GC) reactions could be a triggering factor in CLL, potentially contributing to its pathogenesis. The transcriptional repressors BCL6 (B-Cell CLL/Lymphoma 6) and BACH2 (BTB and CNC Homology 1, Basic Leucine Zipper Transcription Factor 2) are crucial regulators of GC B-cell fate. The double heterozygous Bcl6-/+ Bach2-/+ mice exhibit profound reduction in GC formation in response to T-cell dependent antigen immunization. In GC B cells, the stability of BACH2 protein is regulated by BCL6 and 30% of BACH2 DNA binding sites overlap with BCL6 binding sites. Both proteins are upregulated and interaction between BACH2 and BCL6 represses transcription of PRDM1 (PR Domain Containing 1, With ZNF Domain), a key driver of plasma cell differentiation.
Aims
The aim of the study is to determine the role of these two critical GC B-cells regulators, BCL6 and BACH2 in CLL and investigate whether there is a functional collaboration between them in CLL using a patient sample cohort comprising 102 patients.
Methods
We have analyzed 102 CLL samples using TaqMan quantitative real-time PCR (qPCR) and calculated the relative expression by the 2–ΔΔCt method. A ROC curve was generated to identify the optimal diagnostic cut-off. The expression was then split at this cut-off and the resulting dichotomous variable was included in a survival analysis.
Results
We observed different levels of BCL6 and BACH2 expression throughout the CLL cases analysed. Median RQ (Relative Quantity) was 32.47 (range 4.04-153.29) for BCL6 and 232.62 (range 16.50-1132.30) for BACH2. Interestingly, CLL cases expressing low levels of BCL6 and BACH2 mRNA had significantly shorter overall survival (OS) than high BCL6 and BACH2-expressing samples. Moreover, the low expression of BACH2 and BCL6 specifically decreased OS of CLL patients with mutated IgVH and 11q and 13q deletions. BACH2 mRNA expression negatively correlates to the expression of CD38 (Pearson Correlation coefficient = -.418, p=.011), a poor prognostic factor in CLL. Finally, we identified a positive correlation between BCL6 and BACH2 expression (Pearson correlation coefficient = .335, p=.001), suggesting that these two factors could act synergistically in CLL. We also assessed the impact of BACH2 expression in combination with other variables that are known to be relevant for CLL prognosis (age and 17p deletion) and we identified a prognostic index (PI = 2.6). According to this model, patients with a PI <= 2.6 have a shorter OS compared to patients with a PI > 2.6 (p = 0.004).
Conclusion
Taken together, our study shows the prognostic role of BCL6 and BACH2 in CLL and the possibility of increased B cell receptor signalling due to the lack of Bcl6 and BACH2.
Session topic: E-poster
Keyword(s): B cell chronic lymphocytic leukemia, BCL6
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