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Prepublished online as a Blood First Edition Paper on June 5, 2003; DOI 10.1182/blood-2003-01-0162.
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Blood, 15 September 2003, Vol. 102, No. 6, pp. 2198-2204
NEOPLASIA
FLT3 and MLL intragenic abnormalities in AML reflect a common category of genotoxic stress
Marta Libura,
Vahid Asnafi,
Angela Tu,
Eric Delabesse,
Isabelle Tigaud,
Florence Cymbalista,
Annelise Bennaceur-Griscelli,
Patrick Villarese,
Gabriel Solbu,
Anne Hagemeijer,
Kheira Beldjord,
Olivier Hermine, and
Elizabeth Macintyre
From the Biological and Clinical Hematology Departments, Université Paris V–Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France; Hôpital Edouard Herriot, Lyon, France; Hôtel Dieu, Paris, France; Institut Gustave Roussy, Villejuif, France; European Organisation for the Research and Treatment of Cancer (EORTC) data center, Brussels, Belgium; and the Department of Human Genetics, University of Leuven, Belgium.
MLL rearrangements in acute myeloid leukemia (AML) include translocations and intragenic abnormalities such as internal 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%). Mutation/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 transcripts, 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 predominantly demonstrate PML-RARA and DEK-CAN. FLT3 abnormalities in CBF leukemias 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 demonstrate similar susceptibility to agents that modify chromatin configuration, including topoisomerase II inhibitors and abnormalities involving PML and DEK, with consequent errors in DNA repair. Variant CBF-MYH11 fusions and bcr3 PML-RARA may also be initiated by similar mechanisms.
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