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

Oncogene. 2004 Jan 29;23(4):894-904. doi: 10.1038/sj.onc.1207192.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Adult
  • Aged
  • Blotting, Western
  • Cell Division*
  • DNA, Complementary
  • Gene Expression*
  • Humans
  • Immunohistochemistry
  • Leukemia, Myeloid / enzymology
  • Leukemia, Myeloid / genetics*
  • Leukemia, Myeloid / pathology*
  • Middle Aged
  • Mitogen-Activated Protein Kinases / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Recurrence
  • Reverse Transcriptase Polymerase Chain Reaction


  • DNA, Complementary
  • Mitogen-Activated Protein Kinases