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Regulation And Consequences Of The Loss Of PHLPP1 Tumor Suppressor In Chronic Lymphocytic Leukemia B Cells

TitleRegulation And Consequences Of The Loss Of PHLPP1 Tumor Suppressor In Chronic Lymphocytic Leukemia B Cells
Publication TypeConference Paper
AuthorsKelesoglu, N, Suljagic, M, Efremov, D
Conference Name11th CROATIAN BIOLOGICAL CONGRESS with International Participation
PublisherCroatian Biological Society
Place PublishedSibenik
Abstract

The PH domain leucin-rich repeat protein phosphatase (PHLPP1), a recently identified tumor suppressor
and negative regulator of the Akt kinase, is absent in CLL B-cells. To determine what the consequences
of PHLPP1 loss on BCR signaling are, we downregulated or re-expressed PHLPP1 in lymphoma cell
lines and primary CLL B-cells, respectively. Downregulation of PHLPP1 increased BCR-induced
phosphorylation and activation of the Akt, GSK3 and ERK kinases, whereas re-expression had the
opposite effect. Recent study by O’Hayre et al., suggested that methylation-mediated mechanism may
account for the loss of PHLPP1 expression. However, cases with substantial levels of PHLPP1 mRNA
were also observed, showing PHLPP1 mRNA presence in almost 50% of CLL cases with del13q14,
suggesting that other mechanisms are involved in repressing PHLPP1 protein expression. Incubation of
primary CLL cells with the calpain, proteasome, or caspase inhibitors did not induce any changes in
PHLPP1 protein expression, showing that CLL B-cells do not have an excessive rate of PHLPP1 protein
turnover. We currently challenge the possibility of microRNA regulation of PHLPP1 translation in CLL
cells that express normal levels of PHLPP1 mRNA, but lack the protein expression. Overall, these
observations suggest that the loss of PHLPP1 tumor suppressor in CLL cells may increase responsiveness
to growth and survival stimuli thereby promoting the accumulation of leukemic cells.