Abstract
BackgroundRelapse 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.ResultsAbout 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.ConclusionOur 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.
Highlights
Relapse due to chemoresistant residual disease is a major cause of death in acute myelogenous leukemia (AML)
Our study suggests that AML cells express so far little known or unknown gene products able to protect against chemotherapy, and that naturally occurring pro-apoptotic splice variants can give clues to domains of these proteins that can be pharmacological therapy targets
Identification of genes overexpressed in AML relapse cells More than 25,000 colonies of our leukemia cDNA library were screened with cDNA probes made from pooled leukemia cell RNA from patients with chemosensitive (L1-3) AML and from patients with AML resistant/
Summary
Relapse due to chemoresistant residual disease is a major cause of death in acute myelogenous leukemia (AML). A high frequency of AML relapse is especially observed in certain patient subsets characterized by persistent leukemic disease after the initial induction cycle or by high-risk cytogenetic abnormality [4,5]. Many of these abnormalities affect genes that encode proteins involved in the regulation of gene transcription [1]. These observations are consistent with altered gene expression being involved in chemotherapy resistance This notion is further supported by two recent clinical studies describing association between long-term disease-free survival and particular gene expression profiles identified by cDNA microarray screening [8,9]. Our study suggests that AML cells express so far little known or unknown gene products able to protect against chemotherapy, and that naturally occurring pro-apoptotic splice variants can give clues to domains of these proteins that can be pharmacological therapy targets
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