Transcriptional mechanism of vascular endothelial growth factor-induced expression of protein kinase CβII in chronic lymphocytic leukaemia cells

Al-Sanabra, Ola Mohammed; Duckworth, Andrew D.; Glenn, Mark A.; Brown, Benjamin; Angelillo, Piera; Lee, Kelvin; Herbert, John; Falciani, Francesco; Kalakonda, Nagesh; Slupsky, Joseph R.

doi:10.1038/srep43228

Cited by 6 publications

(6 citation statements)

References 51 publications

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“…Our data show that elevated PKCβ expression in PKCα-KR-transduced cells is driven by elevated Sp1 binding activity at the prkcb promoter. This is similar to what is observed in human CLL cells [ 17 ] and suggests that the mechanisms controlling PKCβ expression are accurately modelled by our system. A further similarity is demonstrated by our experiments using mtm to target the DNA binding activity of SP1.…”

Section: Discussionsupporting

confidence: 87%

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PKCβ Facilitates Leukemogenesis in Chronic Lymphocytic Leukaemia by Promoting Constitutive BCR-Mediated Signalling

Hay

Tarafdar

Holroyd

et al. 2022

Cancers

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B cell antigen receptor (BCR) signalling competence is critical for the pathogenesis of chronic lymphocytic leukaemia (CLL). Defining key proteins that facilitate these networks aid in the identification of targets for therapeutic exploitation. We previously demonstrated that reduced PKCα function in mouse hematopoietic stem/progenitor cells (HPSCs) resulted in PKCβII upregulation and generation of a poor-prognostic CLL-like disease. Here, prkcb knockdown in HSPCs leads to reduced survival of PKCα-KR-expressing CLL-like cells, concurrent with reduced expression of the leukemic markers CD5 and CD23. SP1 promotes elevated expression of prkcb in PKCα-KR expressing cells enabling leukemogenesis. Global gene analysis revealed an upregulation of genes associated with B cell activation in PKCα-KR expressing cells, coincident with upregulation of PKCβII: supported by activation of key signalling hubs proximal to the BCR and elevated proliferation. Ibrutinib (BTK inhibitor) or enzastaurin (PKCβII inhibitor) treatment of PKCα-KR expressing cells and primary CLL cells showed similar patterns of Akt/mTOR pathway inhibition, supporting the role for PKCβII in maintaining proliferative signals in our CLL mouse model. Ibrutinib or enzastaurin treatment also reduced PKCα-KR-CLL cell migration towards CXCL12. Overall, we demonstrate that PKCβ expression facilitates leukemogenesis and identify that BCR-mediated signalling is a key driver of CLL development in the PKCα-KR model.

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Section: Discussionsupporting

confidence: 87%

“…The transcription factor SP1 plays a central role in PRKCB gene regulation in human CLL [ 17 ]. We were interested in determining whether the prkcb gene was similarly regulated by Sp1 in our CLL mouse model.…”

Section: Resultsmentioning

confidence: 99%

PKCβ Facilitates Leukemogenesis in Chronic Lymphocytic Leukaemia by Promoting Constitutive BCR-Mediated Signalling

Hay

Tarafdar

Holroyd

et al. 2022

Cancers

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View full text Add to dashboard Cite

show abstract

“…Our data shows that elevated PKCβ expression in PKCα-KR-transduced cells is driven by elevated Sp1 binding activity at the prkcb promoter. This is similar to what is observed in human CLL cells [17] and suggests that the mechanisms controlling PKCβ expression are accurately modelled by our system. Further similarity is demonstrated by our experiments using mtm to target the DNA binding activity of SP1.…”

Section: Discussionsupporting

confidence: 87%

PKCβ facilitates leukemogenesis in chronic lymphocytic leukaemia by promoting constitutive BCR-mediated signaling

Hay

Tarafdar

Holroyd

et al. 2022

Preprint

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B cell antigen receptor (BCR) signaling competence is critical for pathogenesis of chronic lymphocytic leukemia (CLL). Defining key proteins that facilitate these networks aid in the identification of targets for therapeutic exploitation. We previously demonstrated that reduced PKCα function in mouse hematopoietic stem/progenitor cells (HPSCs) resulted in PKCβII upregulation and generation of a poor-prognostic CLL-like disease. Here, prkcb knockdown in HSPCs leads to reduced survival of PKCα-KR-expressing CLL-like cells, concurrent with reduced expression of the leukemic markers CD5 and CD23. SP1 promotes elevated expression of prkcb in PKCα-KR expressing cells enabling leukemogenesis. Global gene analysis revealed an upregulation of genes associated with B cell activation in PKCα-KR expressing cells, coincident with upregulation of PKCβII: supported by activation of key signaling hubs proximal to the BCR and elevated proliferation. Ibrutinib (BTK inhibitor) or enzastaurin (PKCβII inhibitor) treatment of PKCα-KR expressing cells and primary CLL cells showed similar patterns of Akt/mTOR pathway inhibition, supporting the role for PKCβII in maintaining proliferative signals in our CLL mouse model. Ibrutinib or enzastaurin treatment also reduced PKCα-KR-CLL cell migration towards CXCL12. Overall, we demonstrate that PKCβ expression facilitates leukemogenesis and identify that BCR-mediated signaling is a key driver of CLL development in the PKCα-KR model.

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“…19 The analysis was conducted as previously described. 47 The Jetset database 48 was employed to select more reliable probes from the Affymetrix HG-U133 Plus 2.0 chip for the common genes found. Only expression data from PBMC samples ( n = 1120) and neutrophils ( n = 228) were selected.…”

Section: Methodsmentioning

confidence: 99%

Genetic signature related to heme-hemoglobin metabolism pathway in sepsis secondary to pneumonia

et al. 2019

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Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated inflammatory response to pathogens. Bioinformatics and transcriptomics studies contribute to get a better understanding of the pathogenesis of sepsis. These studies revealed differentially expressed genes (DEGs) in sepsis involved in several pathways. Here we investigated the gene expression profiles of blood leukocytes using three microarray datasets of sepsis secondary to pneumonia, focusing on the heme/hemoglobin metabolism pathway. We demonstrate that the heme/hemoglobin metabolism pathway was found to be enriched in these three cohorts with four common genes ( ALAS2 , AHSP , HBD , and CA1 ). Several studies show that these four genes are involved in the cytoprotection of non-erythrocyte cells in response to different stress conditions. The upregulation of heme/hemoglobin metabolism in sepsis might be a protective response of white cells to the hostile environment present in septic patients (follow-up samples).

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Transcriptional mechanism of vascular endothelial growth factor-induced expression of protein kinase CβII in chronic lymphocytic leukaemia cells

Cited by 6 publications

References 51 publications

PKCβ Facilitates Leukemogenesis in Chronic Lymphocytic Leukaemia by Promoting Constitutive BCR-Mediated Signalling

PKCβ Facilitates Leukemogenesis in Chronic Lymphocytic Leukaemia by Promoting Constitutive BCR-Mediated Signalling

PKCβ facilitates leukemogenesis in chronic lymphocytic leukaemia by promoting constitutive BCR-mediated signaling

Genetic signature related to heme-hemoglobin metabolism pathway in sepsis secondary to pneumonia

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