RRC ID 37796
著者 Yamaguchi H, Hanawa H, Uchida N, Inamai M, Sawaguchi K, Mitamura Y, Shimada T, Dan K, Inokuchi K.
タイトル Multistep pathogenesis of leukemia via the MLL-AF4 chimeric gene/Flt3 gene tyrosine kinase domain (TKD) mutation-related enhancement of S100A6 expression.
ジャーナル Exp Hematol
Abstract OBJECTIVE:Concerning MLL-AF4 leukemogenesis, previous mouse models suggest that the tumorigenesis capacity of MLL-AF4 alone is insufficient for causing leukemia. Based on the finding that an Fms-like tyrosine kinase 3 (Flt3) gene mutation in the tyrosine kinase domain (TKD) was observed in approximately 15% of mixed lineage leukemia (MLL), we investigated synergistic leukemogenesis effects of the two genes in vitro.
MATERIALS AND METHODS:In a mouse interleukin-3 (IL-3)-dependent cell line, 32Dc, expression of MLL-AF4 and mutant Flt3 was induced using a lentiviral vector. We analyzed apoptosis induction in the absence of IL-3 and the granulocyte colony-stimulating factor-related induction of differentiation, gene expression profiling, and the mechanism involved in the synergistic effects of MLL-AF4 and Flt3-TKD.
RESULTS:Neither Flt3-expressing 32Dc (32Dc(Flt3-TKD)) nor MLL-AF4-expressing 32Dc (32Dc(MLL-AF4)) acquired IL-3-independent proliferative capacity in semisolid/liquid media. However, Flt3-TKD+MLL-AF4-expressing 32Dc (32Dc(Flt3-TKD+MLL-AF4)) acquired a non-IL-3-dependent proliferative capacity by inhibiting apoptosis in the two media. The 32Dc(Flt3-TKD) and 32Dc(MLL-AF4) cells differentiated into granulocytes in the presence of granulocyte colony-stimulating factor. However, in the 32Dc(Flt3-TKD+MLL-AF4) cells, there was no differentiation. Subsequently, we performed gene expression profiling. The enhancement of Hox genes expression was not identified. However, expression of S100A6 was synergistically enhanced in the presence of both MLL-AF4 and Flt3-TKD genes. Moreover, anti-S100A6 small interfering RNA downregulated leukemic proliferation.
CONCLUSION:We conclude that their synergistic enhancement of S100A6 expression plays an important role in MLL-AF4-associated leukemogenesis.
巻・号 37(6)
ページ 701-14
公開日 2009-6-1
DOI 10.1016/j.exphem.2009.02.007
PII S0301-472X(09)00055-1
PMID 19463771
MeSH Animals Apoptosis Catalytic Domain / genetics Cell Cycle Proteins / analysis Cell Cycle Proteins / genetics* Cell Line Gene Expression Profiling Gene Expression Regulation, Neoplastic Granulocyte Colony-Stimulating Factor / pharmacology Interleukin-3 / pharmacology Leukemia / etiology* Leukemia / genetics Leukemia / pathology Mice Mutation / physiology* Myeloid-Lymphoid Leukemia Protein / genetics* Oncogene Proteins, Fusion / genetics* S100 Calcium Binding Protein A6 S100 Proteins / analysis S100 Proteins / genetics* fms-Like Tyrosine Kinase 3 / genetics*
IF 2.82
引用数 12
WOS 分野 MEDICINE, RESEARCH & EXPERIMENTAL HEMATOLOGY
リソース情報
ヒト・動物細胞