IMPACT OF THE APOPTOTIC REGULATOR DRAK2 IN CHRONIC LYMPHOCYTIC LEUKEMIA
(Abstract release date: 05/19/16)
EHA Library. soundararajan M. 06/09/16; 132609; E1060
Dr. Meera soundararajan
Contributions
Contributions
Abstract
Abstract: E1060
Type: Eposter Presentation
Background
In chronic lymphocytic leukaemia (CLL), the impaired balance between the pro-apoptotic and anti-apoptotic stimuli is involved in chemorefractoriness and clinical outcome. The low proliferation rate indicates that one of the primary mechanisms during disease development may be apoptotic failure. The apoptotic pathways and CLL proliferation is controlled by a variety of regulator molecules including various protein kinases. DRAK2 belongs to the Death-associated protein kinase (DAPK) family sharing 52% homology with DAP kinase 1 (DAPK1), a heritable predisposing factor in CLL. DRAK2 is expressed exclusively in lymphoid tissue while drak2−/− mice showed five-fold decrease in spleen germinal center compared to their wild-type littermates resulting from increased B-cell apoptosis. Further according to recent studies DRAK2 has been shown to control cell proliferation through its interaction with TβR1 thereby downregulating the smad2/3 mediated signalling.
Aims
The aim of this investigation is to understand the impact of one of the major apoptotic regulators, Death-Associated Protein Kinase-Related 2 (DRAK2) in CLL and its relationship to two distinct cellular networks a) involving TGF-β and b) Zap70-RhoH mediated signalling pathway in CLL
Methods
In our study, 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. DRAK2 expression was then split at this cut-off and the resulting dichotomous variable was included in a survival analysis.
Results
The DRAK2 mRNA expression ranges from 0.16 to 9.26. Interestingly, DRAK2 low-expressing patients showed significantly shorter survival than DRAK2 high-expressing patients (p=0.003). The low expression of DRAK2 is also identified as an adverse prognostic factor within the 13q deleted CLL patients. When we studied the relationship between DRAK2 and critical prognostic factors such as ZAP70 and its interaction partner RhoH, an atypical GTPase which influences the development of CLL, mRNA level of RhoH had no impact on overall survival in our cohort but discovered positive correlation (Pearson’s r=0.36, p=0.00002) between DRAK2 and RhoH mRNA expression levels. Further based on the recent literature, which suggests negative feedback loop regulation between DRAK2 and Transforming growth factor β Receptor I, controlling TGF-β/Smads signalling in solid tumours, we measured the TGFBR1 mRNA expression and found a positive correlation between DRAK2 and TGFBR1 expression (Pearson’s r=0.446, p=0.000003).
Conclusion
Together, our data show for the first time an association between DRAK2 expression and CLL poor prognosis and suggest the possibility of novel TGF-β/DRAK2 apoptotic signalling regulation in CLL. Moreover Zap70-RhoH mediated regulatory mechanism of DRAK2 remains rather complex that needs to be further investigated.
Session topic: E-poster
Type: Eposter Presentation
Background
In chronic lymphocytic leukaemia (CLL), the impaired balance between the pro-apoptotic and anti-apoptotic stimuli is involved in chemorefractoriness and clinical outcome. The low proliferation rate indicates that one of the primary mechanisms during disease development may be apoptotic failure. The apoptotic pathways and CLL proliferation is controlled by a variety of regulator molecules including various protein kinases. DRAK2 belongs to the Death-associated protein kinase (DAPK) family sharing 52% homology with DAP kinase 1 (DAPK1), a heritable predisposing factor in CLL. DRAK2 is expressed exclusively in lymphoid tissue while drak2−/− mice showed five-fold decrease in spleen germinal center compared to their wild-type littermates resulting from increased B-cell apoptosis. Further according to recent studies DRAK2 has been shown to control cell proliferation through its interaction with TβR1 thereby downregulating the smad2/3 mediated signalling.
Aims
The aim of this investigation is to understand the impact of one of the major apoptotic regulators, Death-Associated Protein Kinase-Related 2 (DRAK2) in CLL and its relationship to two distinct cellular networks a) involving TGF-β and b) Zap70-RhoH mediated signalling pathway in CLL
Methods
In our study, 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. DRAK2 expression was then split at this cut-off and the resulting dichotomous variable was included in a survival analysis.
Results
The DRAK2 mRNA expression ranges from 0.16 to 9.26. Interestingly, DRAK2 low-expressing patients showed significantly shorter survival than DRAK2 high-expressing patients (p=0.003). The low expression of DRAK2 is also identified as an adverse prognostic factor within the 13q deleted CLL patients. When we studied the relationship between DRAK2 and critical prognostic factors such as ZAP70 and its interaction partner RhoH, an atypical GTPase which influences the development of CLL, mRNA level of RhoH had no impact on overall survival in our cohort but discovered positive correlation (Pearson’s r=0.36, p=0.00002) between DRAK2 and RhoH mRNA expression levels. Further based on the recent literature, which suggests negative feedback loop regulation between DRAK2 and Transforming growth factor β Receptor I, controlling TGF-β/Smads signalling in solid tumours, we measured the TGFBR1 mRNA expression and found a positive correlation between DRAK2 and TGFBR1 expression (Pearson’s r=0.446, p=0.000003).
Conclusion
Together, our data show for the first time an association between DRAK2 expression and CLL poor prognosis and suggest the possibility of novel TGF-β/DRAK2 apoptotic signalling regulation in CLL. Moreover Zap70-RhoH mediated regulatory mechanism of DRAK2 remains rather complex that needs to be further investigated.
Session topic: E-poster
Abstract: E1060
Type: Eposter Presentation
Background
In chronic lymphocytic leukaemia (CLL), the impaired balance between the pro-apoptotic and anti-apoptotic stimuli is involved in chemorefractoriness and clinical outcome. The low proliferation rate indicates that one of the primary mechanisms during disease development may be apoptotic failure. The apoptotic pathways and CLL proliferation is controlled by a variety of regulator molecules including various protein kinases. DRAK2 belongs to the Death-associated protein kinase (DAPK) family sharing 52% homology with DAP kinase 1 (DAPK1), a heritable predisposing factor in CLL. DRAK2 is expressed exclusively in lymphoid tissue while drak2−/− mice showed five-fold decrease in spleen germinal center compared to their wild-type littermates resulting from increased B-cell apoptosis. Further according to recent studies DRAK2 has been shown to control cell proliferation through its interaction with TβR1 thereby downregulating the smad2/3 mediated signalling.
Aims
The aim of this investigation is to understand the impact of one of the major apoptotic regulators, Death-Associated Protein Kinase-Related 2 (DRAK2) in CLL and its relationship to two distinct cellular networks a) involving TGF-β and b) Zap70-RhoH mediated signalling pathway in CLL
Methods
In our study, 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. DRAK2 expression was then split at this cut-off and the resulting dichotomous variable was included in a survival analysis.
Results
The DRAK2 mRNA expression ranges from 0.16 to 9.26. Interestingly, DRAK2 low-expressing patients showed significantly shorter survival than DRAK2 high-expressing patients (p=0.003). The low expression of DRAK2 is also identified as an adverse prognostic factor within the 13q deleted CLL patients. When we studied the relationship between DRAK2 and critical prognostic factors such as ZAP70 and its interaction partner RhoH, an atypical GTPase which influences the development of CLL, mRNA level of RhoH had no impact on overall survival in our cohort but discovered positive correlation (Pearson’s r=0.36, p=0.00002) between DRAK2 and RhoH mRNA expression levels. Further based on the recent literature, which suggests negative feedback loop regulation between DRAK2 and Transforming growth factor β Receptor I, controlling TGF-β/Smads signalling in solid tumours, we measured the TGFBR1 mRNA expression and found a positive correlation between DRAK2 and TGFBR1 expression (Pearson’s r=0.446, p=0.000003).
Conclusion
Together, our data show for the first time an association between DRAK2 expression and CLL poor prognosis and suggest the possibility of novel TGF-β/DRAK2 apoptotic signalling regulation in CLL. Moreover Zap70-RhoH mediated regulatory mechanism of DRAK2 remains rather complex that needs to be further investigated.
Session topic: E-poster
Type: Eposter Presentation
Background
In chronic lymphocytic leukaemia (CLL), the impaired balance between the pro-apoptotic and anti-apoptotic stimuli is involved in chemorefractoriness and clinical outcome. The low proliferation rate indicates that one of the primary mechanisms during disease development may be apoptotic failure. The apoptotic pathways and CLL proliferation is controlled by a variety of regulator molecules including various protein kinases. DRAK2 belongs to the Death-associated protein kinase (DAPK) family sharing 52% homology with DAP kinase 1 (DAPK1), a heritable predisposing factor in CLL. DRAK2 is expressed exclusively in lymphoid tissue while drak2−/− mice showed five-fold decrease in spleen germinal center compared to their wild-type littermates resulting from increased B-cell apoptosis. Further according to recent studies DRAK2 has been shown to control cell proliferation through its interaction with TβR1 thereby downregulating the smad2/3 mediated signalling.
Aims
The aim of this investigation is to understand the impact of one of the major apoptotic regulators, Death-Associated Protein Kinase-Related 2 (DRAK2) in CLL and its relationship to two distinct cellular networks a) involving TGF-β and b) Zap70-RhoH mediated signalling pathway in CLL
Methods
In our study, 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. DRAK2 expression was then split at this cut-off and the resulting dichotomous variable was included in a survival analysis.
Results
The DRAK2 mRNA expression ranges from 0.16 to 9.26. Interestingly, DRAK2 low-expressing patients showed significantly shorter survival than DRAK2 high-expressing patients (p=0.003). The low expression of DRAK2 is also identified as an adverse prognostic factor within the 13q deleted CLL patients. When we studied the relationship between DRAK2 and critical prognostic factors such as ZAP70 and its interaction partner RhoH, an atypical GTPase which influences the development of CLL, mRNA level of RhoH had no impact on overall survival in our cohort but discovered positive correlation (Pearson’s r=0.36, p=0.00002) between DRAK2 and RhoH mRNA expression levels. Further based on the recent literature, which suggests negative feedback loop regulation between DRAK2 and Transforming growth factor β Receptor I, controlling TGF-β/Smads signalling in solid tumours, we measured the TGFBR1 mRNA expression and found a positive correlation between DRAK2 and TGFBR1 expression (Pearson’s r=0.446, p=0.000003).
Conclusion
Together, our data show for the first time an association between DRAK2 expression and CLL poor prognosis and suggest the possibility of novel TGF-β/DRAK2 apoptotic signalling regulation in CLL. Moreover Zap70-RhoH mediated regulatory mechanism of DRAK2 remains rather complex that needs to be further investigated.
Session topic: E-poster
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