Overexpression of the anti-apoptotic protein AVEN contributes to increased malignancy in hematopoietic neoplasms

AVEN has been identified as an inhibitor of apoptosis, which binds to the adaptor protein, APAF-1, and thereby prevents apoptosome formation and mitochondrial apoptosis. Recent data have demonstrated high expression levels of AVEN messenger RNA in acute leukemias as well as a positive correlation be...

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Bibliographic Details
Published in:	Oncogene Vol. 32; no. 20; pp. 2586 - 2591
Main Authors:	Eißmann, M, Melzer, I M, Fernández, S B M, Michel, G, Hrabě de Angelis, M, Hoefler, G, Finkenwirth, P, Jauch, A, Schoell, B, Grez, M, Schmidt, M, Bartholomae, C C, Newrzela, S, Haetscher, N, Rieger, M A, Zachskorn, C, Mittelbronn, M, Zörnig, M
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 16-05-2013 Nature Publishing Group
Subjects:	631/67/1990/283/2125 692/420/755 Acute lymphoblastic leukemia Acute lymphocytic leukemia Acute myeloid leukemia Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Animals Apaf-1 protein Apoptosis Apoptosis Regulatory Proteins - genetics Apoptosis Regulatory Proteins - metabolism Base Sequence Blood cancer Cell Biology Cell Line, Tumor Cell proliferation Children Development and progression Gene expression Gene Expression Regulation, Leukemic Gene Knockdown Techniques Genes, p53 Human Genetics Humans Inhibitor of apoptosis proteins Internal Medicine Leukemia Lymphatic leukemia Lymphocytes T Lymphoma Lymphoma, T-Cell - genetics Malignancy Medicine Medicine & Public Health Membrane Proteins - genetics Membrane Proteins - metabolism Mice Mice, Inbred C57BL Mice, Transgenic Mitochondria Molecular Sequence Data Molting Myeloblastic leukemia Neoplasia Oncology p53 Protein Physiological aspects Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology Proteins Rodents short-communication T cell receptors Thymocytes - physiology Transgenic mice Tumor cells Tumorigenesis Tumors Xenograft Model Antitumor Assays Xenografts AVEN apoptosis transgenic mice acute lymphoblastic leukemia T-ALL p53
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Summary:	AVEN has been identified as an inhibitor of apoptosis, which binds to the adaptor protein, APAF-1, and thereby prevents apoptosome formation and mitochondrial apoptosis. Recent data have demonstrated high expression levels of AVEN messenger RNA in acute leukemias as well as a positive correlation between AVEN mRNA overexpression and poor prognosis in childhood acute lymphoblastic leukemia. On the basis of these data, we investigated the potential involvement of AVEN in tumorigenesis. First, we confirmed the overexpression of AVEN in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) patient samples. We then established a transgenic mouse model with T-cell-specific overexpression of AVEN, with which we demonstrated the oncogenic cooperation of AVEN with heterozygous loss of p53. Finally, we used a subcutaneous xenograft mouse model to show that AVEN knockdown in the T-ALL cell lines, MOLT-4 and CCRF-CEM, and in the acute myeloblastic leukemia cell line, Kasumi-1, leads to a halt in tumor growth owing to the increased apoptosis and decreased proliferation of tumor cells. Collectively, our data demonstrate that the anti-apoptotic molecule, AVEN, functions as an oncoprotein in hematopoietic neoplasms.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0950-9232 1476-5594
DOI:	10.1038/onc.2012.263