NEOPLASIA FLT3 and MLL intragenic abnormalities in AML reflect a common category of genotoxic stress

MLL rearrangements in acute myeloid leukemia (AML) include translocations and intragenic abnormalities such as in-ternal duplication and breakage induced by topoisomerase II inhibitors. In adult AML, FLT3 internal tandem duplications (ITDs) are more common in cases with MLL intragenic abnormalities (33%) than those with MLL translocation (8%). Muta-tion/deletion involving FLT3 D835 are found in more than 20 % of cases with MLL intragenic abnormalities compared with 10 % of AML with MLL translocation and 5 % of adult AML with normal MLL status. Real-time quantification of FLT3 in 141 cases of AML showed that all cases with FLT3 D835 express high level tran-scripts, whereas FLT3-ITD AML can be divided into cases with high-level FLT3 expression, which belong essentially to the monocytic lineage, and those with relatively low-level expression, which pre-dominantly demonstrate PML-RARA and DEK-CAN. FLT3 abnormalities in CBF leu-kemias with AML1-ETO or CBF-MYH11 were virtually restricted to cases with variant CBF-MYH11 fusion transcripts and/or atypical morphology. These data suggest that the FLT3 and MLL loci dem-onstrate similar susceptibility to agents that modify chromatin configuration, in-cluding topoisomerase II inhibitors and abnormalities involving PML and DEK, with consequent errors in DNA repair. Vari-ant CBF-MYH11 fusions and bcr3 PML-RARA may also be initiated by similar mechanisms. (Blood. 2003;102:2198-2204) © 2003 by The American Society of Hematolog