title: Delineation and molecular characterization of acute myeloid leukemia patients with coduplication of FLT3 and MLL.
abstract: Partial tandem (PTD) and internal tandem duplications (ITD) of the MLL or FLT3 genes respectively, have been demonstrated in acute myeloid leukemia (AML). While occurrence of each of these PTD/ITD seem to confer an unfavorable prognosis, the literature contains only sparse information of the occurrence and the prognosis of simultaneous PTD/ITD of these genes. We have therefore attempted to determine the presence and its consequence in AML and with the further aim of characterizing such patients with respect to other genetic aberrations and to prototype variables in this disease. We analyzed blast cells from 250 adult patients treated at the same institution during a 15-year period for FLT3 ITD and MLL PTD and the duplications were found in 24% and 4%, respectively. The four co-duplicated cases (2%) did not differ with respect to sex, age, FAB-type, or immunophenotype, promoter methylation of p15, E-cadherin (CDH1), Estrogen receptor, MDR1, expression of apoptosis-related or multidrug resistance-related genes, though a trend toward decreased gene expression of MDR1 was observed. Two of the patients had a normal karyotypic analysis, while the remaining two showed aberrations in chromosome 11, one with trisomy 11 and the other with a der (11). The extensive molecular characterization of FLT3/MLL coduplicated patients presented here indicates that, even though they do not differ molecularly from the groups of patients with single ITDs, their prognosis and overall survival is universally poor. More patients are needed to determine whether coduplication has independent clinical implications compared to patients with single ITD/PTD.
authors.affiliation: Department of Hematology, Aarhus University Hospital, Denmark.
authors.forename: Lene Hyldahl
authors.initials: LH
authors.lastname: Olesen
authors.forename: Charlotte Guldborg
authors.initials: CG
authors.lastname: Nyvold
authors.forename: Anni
authors.initials: A
authors.lastname: Aggerholm
authors.forename: Jan Maxwell
authors.initials: JM
authors.lastname: Nørgaard
authors.forename: Per
authors.initials: P
authors.lastname: Guldberg
authors.forename: Peter
authors.initials: P
authors.lastname: Hokland
mesh_terms: D000208:Acute Disease; D000328:Adult; D001483:Base Sequence; D019175:DNA Methylation; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics*; D020440:Gene Duplication; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D016130:Immunophenotyping; D007621:Karyotyping; D007951:Leukemia, Myeloid / Q000235:genetics*; D009154:Mutation; D051788:Myeloid-Lymphoid Leukemia Protein; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011519:Proto-Oncogenes / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D051941:fms-Like Tyrosine Kinase 3
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3