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 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 CBFbeta-MYH11 were virtually restricted to cases with variant CBFbeta-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 CBFbeta-MYH11 fusions and bcr3 PML-RARA may also be initiated by similar mechanisms.
Libura
Marta
M
Laboratoire d'Hématologie, Tour Pasteur, Hôpital Necker, 149-161 rue de Sèvres, 75743 Paris cedex 15, France.
Asnafi
Vahid
V
Tu
Angela
A
Delabesse
Eric
E
Tigaud
Isabelle
I
Cymbalista
Florence
F
Bennaceur-Griscelli
Annelise
A
Villarese
Patrick
P
Solbu
Gabriel
G
Hagemeijer
Anne
A
Beldjord
Kheira
K
Hermine
Olivier
O
Macintyre
Elizabeth
E
D000208:Acute Disease; D001483:Base Sequence; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004273:DNA, Neoplasm / Q000032:analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons; D017353:Gene Deletion; D020440:Gene Duplication; D015973:Gene Expression Regulation, Leukemic; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007948:Leukemia, Monocytic, Acute / Q000235:genetics; D007951:Leukemia, Myeloid / Q000235:genetics*; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011519:Proto-Oncogenes; D012334:RNA, Neoplasm / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D014157:Transcription Factors; D014178:Translocation, Genetic; D014314:Trisomy; D051941:fms-Like Tyrosine Kinase 3
D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D011518:Proto-Oncogene Proteins; D012334:RNA, Neoplasm; 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; D004250:DNA Topoisomerases, Type II