Partial tandem duplications of the MLL gene are detectable in peripheral blood and bone marrow of nearly all healthy donors.

Partial tandem duplication within the MLL gene has recently been described as a novel genetic alteration in acute myeloid leukemia (AML). It has been associated with trisomy of chromosome 11, but was also identified in AML patients with normal karyotypes. The current study was performed to investigate whether MLL duplications are restricted to AML, and hence whether they may also occur in normal hematopoietic cells. MLL-duplication transcripts were analyzed by nested reverse-transcriptase polymerase chain reaction (RT-PCR) in peripheral blood in two groups of 45 and 20 patients, respectively, as well as in two bone marrow samples from healthy volunteers. Duplications were detected in two independent nested RT-PCR experiments in the peripheral blood samples of 38 of 45 (84%) and 20 of 20 (100%) of the two groups and in both bone marrow samples. On this basis, MLL duplications seem to occur frequently in a subset of cells in normal hematopoiesis. The type of partially duplicated MLL transcripts varied substantially. Three transcripts were identical to those known from AML. In addition, four new transcripts were characterized. Three of these four were in frame and potentially translatable. MLL duplications were also detected by seminested genomic PCR with intron 9- and intron 1-specific primers in 20 of 20 peripheral blood samples studied, indicating that the duplications are genomically fixed at the DNA level and are not an RT-PCR artifact. In summary, MLL duplications are regularly generated by homologous ALU recombination in a small number of hematopoietic cells of most or even all healthy donors. These data suggest that MLL duplications are not implicated in the malignant transformation in AML, or alternatively, that only a few cells will acquire additional oncogenic mutations necessary to establish the malignant phenotype of AML.