molecular mechanisms supporting minimal-residual disease of 11q23/MLL-rearranged leukemia cells in bone marrow

Flt3在急性淋巴细胞白血病中高表达，11q23/MLL重排对化疗无效。11q23/MLL重排白血病细胞与高水平表达FL的骨髓基质细胞之间的Flt3/Flt3配体(FL)相互作用可诱导11q23/MLL重排白血病细胞进入对抗白血病药物耐药的休眠状态。转化生长因子-β1和FL协同诱导11q23/MLL重排白血病细胞转化生长因子-β1-mRNA的表达。此外，骨髓基质细胞和白血病细胞分泌的转化生长因子-β1与FL协同诱导11q23/MLL重排白血病进入更强的休眠状态。在11q23/MLL重排白血病细胞中，在慢性粒细胞白血病干细胞维持中起重要作用的Forkhead O转录因子(FOXO3a)的核定位受到转化生长因子-β1和FL的刺激而降低。

FLT3 is highly expressed in acute lymphoblastic leukemia with the 11q23/MLL rearrangement refractory to chemotherapy. The FLT3/FLT3-ligand (FL) interaction between 11q23/MLL-rearranged leukemia cells and bone marrow stromal cells expressing FL at high levels induce 11q23/MLL-rearranged leukemia cells into dormant status resistant to anti-leukemic agents. TGF-beta1 and FL cooperatively induce TGF-beta1-mRNA expression of 11q23/MLL-rearranged leukemia cells. Moreover, TGF-beta1 secreted by both bone marrow stromal cells and leukemia cells induce 11q23/MLL-rearranged leukemia into dormant status more strongly in cooperation with FL. Nuclear localization of forkhead O transcription factors (FOXO3a), that plays an important role in the maintenance of chronic myeloid leukemia stem cells, is decreased by stimulation of TGF-beta1 and FL in 11q23/MLL-rearranged leukemia cells.