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


CONCLUSIONS
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.
Huang
Tien-sheng
TS
Department of Molecular Biology, University of Bergen, Bergen, Norway. david.huang@gades.uib.no
Myklebust
Line M
LM
Kjarland
Endre
E
Gjertsen
Bjørn Tore
BT
Pendino
Frederic
F
Bruserud
Øystein
Ø
Døskeland
Stein Ove
SO
Lillehaug
Johan R
JR
D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics; D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005091:Exons / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D052138:Genes, Neoplasm; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology*; D008213:Lymphocyte Activation / Q000235:genetics*; D008969:Molecular Sequence Data; D009364:Neoplasm Recurrence, Local; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D036341:Intercellular Signaling Peptides and Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; C119380:lens epithelium-derived growth factor; D000242:Cyclic AMP; D003630:Daunorubicin