Constitutive Fms-like tyrosine kinase 3 activation results in specific changes in gene expression in myeloid leukaemic cells.
Constitutively activating internal tandem duplication (ITD) mutations of the receptor tyrosine kinase FLT3 (Fms-like tyrosine kinase 3) play an important role in leukaemogenesis. We have examined, by cDNA microarray analysis, the changes in gene expression induced by FLT3/ITD or constitutively activated wild type FLT3 signalling. A limited set of genes was consistently affected by FLT3 inhibition. In confirmation of their FLT3 dependence, these genes returned toward pretreatment levels of expression after reversal of FLT3 inhibition. Several of the most significantly affected genes are involved in the RAS/mitogen-activated protein kinase, Janus kinase/signal transducer and activator of transcription and phosphatidylinositol 3 kinase (PI3K)/AKT pathways. These data suggest that constitutively activated FLT3 works through multiple signal transduction pathways. PIM1, MYC and CCND3 were chosen from this gene set to explore their biological roles. Knock-down of these genes by small interfering RNA showed that these genes play important roles in constitutively activated FLT3 expressing cells. The alterations of the gene expression profiles in these cells help to further elucidate the mechanisms of FLT3-mediated leukaemogenesis.
Kim
Kyu-Tae
KT
Department of Oncology, Johns Hopkins University School of Medicine, Bethesda, MD, USA.
Baird
Kristin
K
Davis
Sean
S
Piloto
Obdulio
O
Levis
Mark
M
Li
Li
L
Chen
Peili
P
Meltzer
Paul
P
Small
Donald
D
D049109:Cell Proliferation; D056743:Cyclin D3; D016213:Cyclins / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007951:Leukemia, Myeloid / Q000201:enzymology*; D009363:Neoplasm Proteins / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction / Q000379:methods; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism*
C534696:CCND3 protein, human; D056743:Cyclin D3; D016213:Cyclins; D018076:DNA, Complementary; D004273:DNA, Neoplasm; C489427:MYC protein, human; D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1