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Molecular typing of adult acute myeloid leukaemia: significance of translocations, tandem duplications, methylation, and selective gene expression profiling
Author(s) -
Olesen Lene Hyldahl,
Aggerholm Anni,
Andersen Bodil Lind,
Nyvold Charlotte Guldborg,
Guldberg Per,
Nørgaard Jan Maxwell,
Hokland Peter
Publication year - 2005
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2005.05791.x
Subject(s) - chromosomal translocation , gene duplication , cdh1 , biology , tandem exon duplication , cancer research , gene , oncology , medicine , genetics , cell , cadherin
Summary 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.

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