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  • Original Paper
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Common alterations in gene expression and increased proliferation in recurrent acute myeloid leukemia

Abstract

Recurrent disease following high-dose chemotherapy is a major problem in patients with acute myeloid leukemia (AML). To identify its characteristics, we performed expression profiling in blasts from untreated AML and relapse, using a specific cDNA microarray comprising 4128 genes generated by cDNA subtraction supplemented with cancer-associated genes. Expression analysis of 18 AML bone marrow specimens showed that recurrent AML is commonly associated with the mRNA expression changes in a set of 58 genes. Increased cellular proliferation was indicated by the overexpression of the transferrin receptor, proliferating cell nuclear antigen, and G1 cyclins. An immunohistochemical study for Ki-67-positive blasts in 18 paired bone marrow biopsy samples confirmed a highly significant (P<0.0001) increase in the proliferation fraction at relapse. In addition, we found enhanced activation of the RAF/MEK/ERK cascade as mRNAs of MKP-1, c-jun, c-fos, and egr-1 were significantly increased at relapse. Immunohistochemistry and immunoblotting analyses for biphosphorylated ERK1/2 protein provide additional evidence for enhanced activation of the RAF/MEK/ERK pathway. The degree of increase is significantly correlated with the increased proliferation. Furthermore, the genes identified provide a rationale for further studies on predictive diagnosis and therapeutic intervention.

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Acknowledgements

We thank E Lamont, C Buck, and H Denk for critically reading the manuscript; and B Strohmeier, K Meister, and K Wagner for technical assistance. This work was supported in part by the Austrian FWF Grant P-15300 (G Hoefler), S-7401MOB, and the Lore Saldow fund.

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Correspondence to Gerald Hoefler.

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Staber, P., Linkesch, W., Zauner, D. et al. Common alterations in gene expression and increased proliferation in recurrent acute myeloid leukemia. Oncogene 23, 894–904 (2004). https://doi.org/10.1038/sj.onc.1207192

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