Peptide microarray profiling identifies phospholipase C gamma 1 (PLC-γ1) as a potential target for t(8;21) AML
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Hasan Mahmud1,2, Frank J.G. Scherpen1, Tiny Meeuwsen de Boer1, Harm-Jan Lourens1, Caroline Schoenherr3, Matthias Eder3, Michaela Scherr3, Victor Guryev4 and Eveline S. De Bont1
1Department of Pediatric Oncology/Hematology, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
2Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
3Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
4Laboratory of Genome Structure and Aging, European Research Institute for the Biology of Aging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Eveline S. De Bont, email: [email protected]
Keywords: AML, leukemia, t(8;21), PLC-γ1, peptide microarray
Received: February 21, 2017 Accepted: May 01, 2017 Published: June 27, 2017
The t(8;21) (q22;q22) chromosomal translocation is one of the most frequent genetic alterations in acute myeloid leukemia (AML) which has a need for improved therapeutic strategies. We found PLC-γ1 as one of the highest phosphorylated peptides in t(8;21) AML samples compared to NBM or CN-AML in our previous peptide microarray. PLC-γ1 is known to play a role in cancer progression, however, the impact of PLC-γ1 in AML is currently unknown. Therefore, we aimed to study the functional role of PLC-γ1 by investigating the cellular growth, survival and its underlying mechanism in t(8;21) AML.
In this study, PLC-γ1 expression was significantly higher in t(8;21) AML compared to other karyotypes. The PLC-γ1 protein expression was suppressed in AML1-ETO knock down cells indicating that it might induce kasumi-1 cell death. ShRNA-mediated PLC-γ1 knockdown in kasumi-1 cells significantly blocked cell growth, induced apoptosis and cell cycle arrest which was explained by the increased activation of apoptotic related and cell cycle regulatory protein expressions. Gene expression array analysis showed the up-regulation of apoptotic and DNA damage response genes together with the downregulation of cell growth, proliferation and differentiation genes in the PLC-γ1 suppressed kasumi-1 cells, consistent with the observed phenotypic effects. Importantly, PLC-γ1 suppressed kasumi-1 cells showed higher chemosensitivity to the chemotherapeutic drug treatments and lower cell proliferation upon hypoxic stress.
Taken together, these in vitro finding strongly support an important role for PLC-γ1 in the survival of t(8;21) AML mimicking kasumi-1 cells and identify PLC-γ1 as a potential therapeutic target for t(8;21) AML treatment.
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