Abstract
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.
Highlights
Acute myeloid leukemia (AML) forms a spectrum of diseases that share clinical and pathological features, which arise from a wide diversity of abnormalities, including mutations, cytogenetic abnormalities, and epigenetic changes [1,2,3,4]
We found PLC-γ1 as one of the highest phosphorylated peptides in t(8;21) AML samples compared to Normal bone marrow (NBM) or cytogenetically normal (CN-AML) in our previous peptide microarray
Phospholipase C-gamma 1 (PLC-γ1_Y783) was identified from our previous peptide array as one of the highest phosphorylated peptides in t(8;21) AML samples when compared to NBM or CNAML (Figure 1A)
Summary
Acute myeloid leukemia (AML) forms a spectrum of diseases that share clinical and pathological features, which arise from a wide diversity of abnormalities, including mutations, cytogenetic abnormalities, and epigenetic changes [1,2,3,4]. The relapse rate of t(8;21) AML in children is about 30% and long-term survival rate is about 75% which indicate the need for improved therapeutic strategies [14,15,16,17,18]. Molecular analysis such as next-generation sequencing and transcriptome analysis have revealed many previously unknown recurrent mutations and additional mechanistic insights such as alternations in the epigenetic status, still the results as well as the prediction of drug response to treatments with specific newly designed inhibitors in AML are missing. We performed peptide microarray profiling array as we did previously [20, 22] for t(8;21) AML and found that phospholipase C-gamma 1 (PLC-γ1) at tyrosine 783 was highly phosphorylated in these leukemia cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
