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Open Access 01-12-2007 | Research

LEDGF/p75 has increased expression in blasts from chemotherapy-resistant human acute myelogenic leukemia patients and protects leukemia cells from apoptosis in vitro

Authors: Tien-sheng Huang, Line M Myklebust, Endre Kjarland, Bjørn Tore Gjertsen, Frederic Pendino, Øystein Bruserud, Stein Ove Døskeland, Johan R Lillehaug

Published in: Molecular Cancer | Issue 1/2007

Abstract

Background

Relapse due to chemoresistant residual disease is a major cause of death in acute myelogenous leukemia (AML). The present study was undertaken to elucidate the molecular mechanisms of chemoresistance by comparing differential gene expression in blasts from patients with resistant relapsing AML and chemosensitive AML.

Results

About 20 genes were identified as preferentially expressed in blasts pooled from patients with resistant disease, as compared to chemosensitive AML blasts, based on differential gene expression screening. Half of these genes encoded proteins related to protein translation, of these a novel protein related to the ribosomal stalk protein P0. Other upregulated mRNAs coded for cytochrome C oxidase III, the transcription factors ERF-2/TIS11d, and the p75 and p52 splice variants of Lens Epithelial Derived Growth Factor (LEDGF). Analysis of blasts from single patients disclosed that LEDGF/p75 was the most consistently upregulated mRNA in resistant AML. Transfection experiments demonstrated that LEDGF/p75 and p52b antagonized daunorubicin-induced and cAMP-induced apoptosis in an AML cell line. Also HEK-293 cells were protected against daunorubicin by LEDGF/p75 and p52b, whereas LEDGF/p52 splice variants lacking exon 6 had proapoptotic effects. Interestingly, full length LEDGF/p75 protected against truncated pro-apoptotic LEDGF/p75.

Conclusion

Our results provide evidence for an association between the overexpression of genes encoding survival proteins like LEDGF/p75 and chemo-resistance in acute myelogenous leukemia. LEDGF/p75 has previously not been shown to protect against chemotherapy, and is a potential drug target in AML.

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Title: LEDGF/p75 has increased expression in blasts from chemotherapy-resistant human acute myelogenic leukemia patients and protects leukemia cells from apoptosis in vitro
Authors: Tien-sheng Huang
Line M Myklebust
Endre Kjarland
Bjørn Tore Gjertsen
Frederic Pendino
Øystein Bruserud
Stein Ove Døskeland
Johan R Lillehaug
Publication date: 01-12-2007
Publisher: BioMed Central
Published in: Molecular Cancer / Issue 1/2007
Electronic ISSN: 1476-4598
DOI: https://doi.org/10.1186/1476-4598-6-31

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