PKCβ Facilitates Leukemogenesis in Chronic Lymphocytic Leukaemia by Promoting Constitutive BCR-Mediated Signalling
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 i...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-12-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/23/6006 |
| _version_ | 1797463499198169088 |
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| author | Jodie Hay Anuradha Tarafdar Ailsa K. Holroyd Hothri A. Moka Karen M. Dunn Alzahra Alshayeb Bryony H. Lloyd Jennifer Cassels Natasha Malik Ashfia F. Khan IengFong Sou Jamie Lees Hassan N. B. Almuhanna Nagesh Kalakonda Joseph R. Slupsky Alison M. Michie |
| author_facet | Jodie Hay Anuradha Tarafdar Ailsa K. Holroyd Hothri A. Moka Karen M. Dunn Alzahra Alshayeb Bryony H. Lloyd Jennifer Cassels Natasha Malik Ashfia F. Khan IengFong Sou Jamie Lees Hassan N. B. Almuhanna Nagesh Kalakonda Joseph R. Slupsky Alison M. Michie |
| author_sort | Jodie Hay |
| collection | DOAJ |
| description | 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, <i>prkcb</i> 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 <i>prkcb</i> 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. |
| first_indexed | 2024-03-09T17:51:34Z |
| format | Article |
| id | doaj.art-a6177b332f8b4b31a25e7bb1b6ba6562 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T17:51:34Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-a6177b332f8b4b31a25e7bb1b6ba65622023-11-24T10:42:15ZengMDPI AGCancers2072-66942022-12-011423600610.3390/cancers14236006PKCβ Facilitates Leukemogenesis in Chronic Lymphocytic Leukaemia by Promoting Constitutive BCR-Mediated SignallingJodie Hay0Anuradha Tarafdar1Ailsa K. Holroyd2Hothri A. Moka3Karen M. Dunn4Alzahra Alshayeb5Bryony H. Lloyd6Jennifer Cassels7Natasha Malik8Ashfia F. Khan9IengFong Sou10Jamie Lees11Hassan N. B. Almuhanna12Nagesh Kalakonda13Joseph R. Slupsky14Alison M. Michie15School of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UKSchool of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UKSchool of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UKSchool of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UKSchool of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UKInstitute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7BE, UKInstitute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7BE, UKSchool of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UKSchool of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UKSchool of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UKSchool of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UKSchool of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UKSchool of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UKInstitute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7BE, UKInstitute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7BE, UKSchool of Cancer Sciences, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UKB 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, <i>prkcb</i> 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 <i>prkcb</i> 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.https://www.mdpi.com/2072-6694/14/23/6006CLLPKCβSP1BCR signallingleukemogenesis |
| spellingShingle | Jodie Hay Anuradha Tarafdar Ailsa K. Holroyd Hothri A. Moka Karen M. Dunn Alzahra Alshayeb Bryony H. Lloyd Jennifer Cassels Natasha Malik Ashfia F. Khan IengFong Sou Jamie Lees Hassan N. B. Almuhanna Nagesh Kalakonda Joseph R. Slupsky Alison M. Michie PKCβ Facilitates Leukemogenesis in Chronic Lymphocytic Leukaemia by Promoting Constitutive BCR-Mediated Signalling Cancers CLL PKCβ SP1 BCR signalling leukemogenesis |
| title | PKCβ Facilitates Leukemogenesis in Chronic Lymphocytic Leukaemia by Promoting Constitutive BCR-Mediated Signalling |
| title_full | PKCβ Facilitates Leukemogenesis in Chronic Lymphocytic Leukaemia by Promoting Constitutive BCR-Mediated Signalling |
| title_fullStr | PKCβ Facilitates Leukemogenesis in Chronic Lymphocytic Leukaemia by Promoting Constitutive BCR-Mediated Signalling |
| title_full_unstemmed | PKCβ Facilitates Leukemogenesis in Chronic Lymphocytic Leukaemia by Promoting Constitutive BCR-Mediated Signalling |
| title_short | PKCβ Facilitates Leukemogenesis in Chronic Lymphocytic Leukaemia by Promoting Constitutive BCR-Mediated Signalling |
| title_sort | pkcβ facilitates leukemogenesis in chronic lymphocytic leukaemia by promoting constitutive bcr mediated signalling |
| topic | CLL PKCβ SP1 BCR signalling leukemogenesis |
| url | https://www.mdpi.com/2072-6694/14/23/6006 |
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