Increased expression of amyloid precursor protein promotes proliferation and migration of AML1/ETO-positive leukemia cells and be inhibited by panobinostat

Abstract

Amyloid precursor protein (APP) is a highly conserved integral membrane protein extensively expressed in various types of cells. Previously we found that overexpression of APP in patients with AML1/ETO-positive acute myeloid leukemia (AML) associated with a higher incidence of extramedullary infiltrationin and indicate a poor prognosis. In this study, we attempted to define the roles of APP in AML1/ETO-positive leukemia cells. Western blotting and qRT-PCR analysis showed that protein levels of APP are significantly higher in Kasumi-1, a t(8;21)/ AML1/ETO-positive M2-type AML cell line. Stable knockdown of APP by lentivirus-based RNA interference (RNAi) dramatically impaired colony-formation and migration ability of Kasumi-1 cells, whereas APP knockdown had very little effect on cell viability, apoptosis, cell cycle and differentiation. We further explored whether the pan-histone deacetylase inhibitor panobinostat could deplete the protein levels of APP in Kasumi-1 cells. Treatment with panobinostat caused depletion of APP in Kasumi-1 cells. These findings indicate that overexpression of APP is involved in promoting proliferation and migration of AML1/ETO-positive leukemia cells and can be inhibited by panobinostat, which provide an attractive prospect for treatment of AML1/ETO-positive AML. Key words: APP, Kasumi-1, AML1/ETO, panobinostatAcute myeloid leukemia (AML) with t(8;21)(q22;q22) is a specific subtype, and is frequently associated with M2 subtype according to the French-American-British (FAB) classification. The t(8;21)(q22;q22) involves the AML1 gene on chromosome 21 and the ETO gene on chromosome 8 generating the AML1/ETO fusion gene. AML with AML1/ ETO-positive is generally considered as a favorable prognosis particularly with high-dose cytosine arabinoside (Ara-C) consolidation chemotherapy. However, the treatment outcomes are not satisfactory for a high relapse rate within one year about 30% or more[1-2]. As for the assessment of prognosis of AML patients with AML1/ETO-positive, many other elements including additional chromosomal aberrations, individual genes mutations, and clinical course should be considered.Amyloid precursor protein (APP) is a highly evolutionary conserved protein. The gene for human APP is on chromosome 21q21.3 and encode a type I integral membrane protein.APP can participate in transmembrane signaling events due to its highly conserved extracellular and intracellular domains, which plays important roles in many physiological processes [3][4][5][6][7]. Many recent studies have indicated that APP is overexpressed commonly in solid tumors and mainly involved in promoting proliferation of tumor cells, including oral squamous cell carcinoma [8], pancreatic cancer cells [9], parathyroid tumor [10], and breast cancer [11]. APP was also found significantly higher in AML with abnormal chromosome 21 compared to a control group of AML with normal cytogenetics using oligonucleotide arrays [12]. Our previous study found that overexpression of APP in patients with AML1/ETO-positive AML has ...

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Allogeneic hematopoietic stem cell transplantation for relapsed acute myeloid leukemia in ETO positive with reduced-intensity conditioning

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Epigenome-Based Drug Repositioning in Acute Myeloid Leukemia

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