Common alterations in gene expression and increased proliferation in recurrent acute myeloid leukemia.
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.
Staber
Philipp Bernhard
PB
Division of Hematology, Department of Internal Medicine, Graz, Austria.
Linkesch
Werner
W
Zauner
Dorothea
D
Beham-Schmid
Christine
C
Guelly
Christian
C
Schauer
Silvia
S
Sill
Heinz
H
Hoefler
Gerald
G
D000208:Acute Disease; D000328:Adult; D000368:Aged; D015153:Blotting, Western; D002455:Cell Division; D018076:DNA, Complementary; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D007951:Leukemia, Myeloid / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012008:Recurrence; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018076:DNA, Complementary; D020928:Mitogen-Activated Protein Kinases