Biology subjects

Dunn, K. M.

Publications and source records attributed to Dunn, K. M..

3 recordsLinked to original sources

bioRxiv2022

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

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 PKC function in mouse hematopoietic stem/progenitor cells (HPSCs) resulted in PKC{beta}II upregulation and generation of a poor-prognostic CLL-like disease. Here, prkcb knockdown in HSPCs leads to reduced survival of PKC-KR-expressing CLL-like cells, concurrent with reduced expression of the leukemic markers CD5 and CD23. SP1 promotes elevated expression of prkcb in PKC-KR expressing cells enabling leukemogenesis. Global gene analysis revealed an upregulation of genes associated with B cell activation in PKC-KR expressing cells, coincident with upregulation of PKC{beta}II: supported by activation of key signaling hubs proximal to the BCR and elevated proliferation. Ibrutinib (BTK inhibitor) or enzastaurin (PKC{beta}II inhibitor) treatment of PKC-KR expressing cells and primary CLL cells showed similar patterns of Akt/mTOR pathway inhibition, supporting the role for PKC{beta}II in maintaining proliferative signals in our CLL mouse model. Ibrutinib or enzastaurin treatment also reduced PKC-KR-CLL cell migration towards CXCL12. Overall, we demonstrate that PKC{beta} expression facilitates leukemogenesis and identify that BCR-mediated signaling is a key driver of CLL development in the PKC-KR model. Statement of SignificancePKC{beta} facilitates leukemogenesis of CLL, driven through an SP1-regulated transcriptional program and promotes BCR signaling. Thus far, PKC{beta} is the only kinase within the BCR signaling pathway, a key pathway in driving CLL pathogenesis, implicated in the generation of neoplastic B lineage cells.

cancer biology↗

bioRxiv2022

mTORC1 activity is essential for disease progression in chronic lymphocytic leukemia

The precise role of mechanistic target of rapamycin complex 1 (mTORC1) during chronic lymphocytic leukemia (CLL) pathogenesis remains to be elucidated. Targeted deletion of mTORC1 component Raptor in adult mice reveals that mTORC1 function is essential for initiation and maintenance of CLL. Raptor-deficient bone marrow-derived PKC-KR transduced haemopoietic progenitors failed to generate a CLL-like disease in vitro, due to an inability to overcome the mTORC1-mediated block in B cell lineage commitment. Induction of Raptor-deficiency in NSG mice transplanted with Mx1-Raptor BM-derived PKC-KR transduced cells after disease was established, revealed a reduced CLL-like disease load and a significant increase in survival in the mice. Interestingly in mice transplanted with an aggressive CLL-like disease, rapamycin treatment reduced disease burden more effectively than AZD2014 (dual mTORC1/2 inhibitor), indicating a skew towards mTORC1 sensitivity with more aggressive leukemic disease. Rapamycin efficiently targeted the translation elongation axis eEF2/eEF2K downstream of mTORC1, resulting in eEF2 inactivation through induction of eEF2T56 phosphorylation. Rapamycin treatment of primary CLL cells halted proliferation, modulated eEF2K/eEF2 phosphorylation and inhibited MCL1 expression. Our studies demonstrate that mTORC1 plays an essential role in leukemia progression in vitro and in vivo in our CLL mouse model, with evidence for increased rapamycin sensitivity in aggressive secondary CLL transplants. Furthermore, the suppression of translation elongation through inactivation of eEF2 may offer a novel therapeutic target for blocking CLL progression.

cancer biology↗

bioRxiv2018

Back pain, mental health and substance use are associated in adolescents

BackgroundDuring adolescence, prevalence of pain and health risk factors such as smoking, alcohol use, and poor mental health rise sharply. While these risk factors and mental health are accepted public health concerns, the same is not true for pain. The aim of this study was to describe the relationship between back pain and health risk factors in adolescents.\n\nMethodsCross-sectional data from the Healthy Schools Healthy Futures study, and the Australian Child Wellbeing Project was used. The mean age of participants was 14-15 years. Children were stratified according to the frequency they experienced back pain over the past 6 months. Within each strata, the proportion of children that reported drinking alcohol or smoking in the past month and the proportion that experienced feelings of anxiety or depression was reported. Test-for-trend analyses assessed whether increasing frequency of pain was associated with health risk factors.\n\nResultsData from approximately 2,500 and 3,900 children in the two studies was analysed. Larger proportions of children smoked or drank alcohol within each strata of increasing pain frequency. The trend with report of anxiety and depression was less clear, although there was a marked difference between the children that reported pain rarely or never, and those that experienced back pain more frequently.\n\nConclusionTwo large, independent samples show Australian adolescents that experience back pain more frequently are also more likely to smoke, drink alcohol and report feelings of anxiety and depression. Pain appears to be part of the picture of general health risk in adolescents.\n\nWhat is already known on this subject?The prevalence of back pain rises steeply during the adolescent years, and is responsible for considerable personal impact in a substantial minority. During this time, indicators of adverse health risk such as smoking, alcohol use, anxiety and depression also increase in prevalence. Pain and lifestyle-related health risk factors can have ongoing consequences that stretch into adulthood.\n\nWhat this study adds?This study shows a close relationship between increasing pain frequency, and tendency to engage in health risk behaviours and experience indicators of poor mental health in adolescents. This study shows that pain may be an important consideration in understanding the general health, and health risk in adolescents.

epidemiology↗