Three-way translocation involves MLL, MLLT3, and a novel cell cycle control gene, FLJ10374, in the pathogenesis of acute myeloid leukemia with t(9;11;19)(p22;q23;p13.3).
The MLL gene, at 11q23, undergoes chromosomal translocation with a large number of partner genes in both acute lymphoblastic and acute myeloid leukemia (AML). We report a novel t(9;11;19)(p22;q23;p13.3) disrupting MLL in an infant AML patient. The 5' end of MLL fused to chromosome 9 sequences on the der(11), whereas the 3' end was translocated to chromosome 19. We developed long-distance inverse-polymerase chain reaction assays to investigate the localization of the breakpoints on der(11) and der(19). We found that intron 5 of MLL was fused to intron 5 of MLLT3 at the der(11) genomic breakpoint, resulting in a novel in-frame MLL exon 5-MLLT3 exon 6 fusion transcript. On the der(19), a novel gene annotated as FLJ10374 was disrupted by the breakpoint. Using reverse transcription-polymerase chain reaction analysis, we showed that FLJ10374 is ubiquitously expressed in human cells. Transfection of the FLJ10374 protein in different cell lines revealed that it localized exclusively to the nucleus. In serum-starved NIH-3T3 cells, the expression of FLJ10374 decreased the rate of the G1-to-S transition of the cell cycle, whereas the suppression of FLJ10374 through short interfering RNA increased cell proliferation. These results indicate that FLJ10374 negatively regulates cell cycle progression and proliferation. Thus, a single chromosomal rearrangement resulting in formation of the MLL-MLLT3 fusion gene and haplo-insufficiency of FLJ10374 may have cooperated to promote leukemogenesis in AML with t(9;11;19).
Vieira
Luís
L
Centro de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisboa, Portugal. luis.vieira@insa.min-saude.pt
Sousa
Ana C
AC
Matos
Paulo
P
Marques
Bárbara
B
Alaiz
Helena
H
Ribeiro
Maria J
MJ
Braga
Paula
P
da Silva
Maria G
MG
Jordan
Peter
P
D000208:Acute Disease; D000595:Amino Acid Sequence; D001483:Base Sequence; D002880:Chromosomes, Human, Pair 11; D002899:Chromosomes, Human, Pair 9; D004247:DNA; D005091:Exons; D005260:Female; D018816:Genes, cdc; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D007951:Leukemia, Myeloid / Q000235:genetics*; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D014178:Translocation, Genetic
C497422:KMT2A protein, human; C489901:MLLT3 protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger; D051788:Myeloid-Lymphoid Leukemia Protein; D004247:DNA; D011495:Histone-Lysine N-Methyltransferase