Molecular typing of adult acute myeloid leukaemia: significance of translocations, tandem duplications, methylation, and selective gene expression profiling.
Although a number of molecular aberrations have been described in acute myeloid leukaemia (AML), no study has yet determined their relative prognostic importance. We have analysed blast cells from 250 adult patients treated at the same institution during a 15-year period. Balanced translocations were detected by multiplex polymerase chain reaction in 13% of the cases. Internal tandem duplication (ITD) of the FLT3 gene and partial tandem duplication of the MLL gene were found in 24% and 4%, respectively. Promoter hypermethylation of the P15, CDH1, ER and MDR1 genes was observed in 71%, 64%, 40% and 4%, respectively. Compared with normal bone marrow, the chemotherapy resistance protein MRP1 and apoptosis related genes BAX and CASPASE3 were found to be overexpressed in AML blasts. Univariate analysis revealed that the most important determinants of prognosis were presence of balanced translocations, age, white blood cell count and extramedullary disease, in order of statistical significance. In a multivariate analysis, balanced translocations retained their prognostic significance and FLT3 ITD as well as high gene expression of MDR1 were negative prognostic factors. From these data, which are the first to compare these molecular aberrations directly, we conclude that, when a battery of molecular changes is evaluated for upfront significance in AML, recurrent translocations are of prime importance for treatment outcome.
Olesen
Lene Hyldahl
LH
Department of Haematology, Aarhus University Hospital, Aarhus, Denmark.
Aggerholm
Anni
A
Andersen
Bodil Lind
BL
Nyvold
Charlotte Guldborg
CG
Guldberg
Per
P
Nørgaard
Jan Maxwell
JM
Hokland
Peter
P
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D020869:Gene Expression Profiling; D019450:Genes, MDR; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D016019:Survival Analysis; D020080:Tandem Repeat Sequences / Q000235:genetics*; D014178:Translocation, Genetic; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3