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

Research Project

Project/Area Number	22591153
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Single-year Grants
Section	一般
Research Field	Pediatrics
Research Institution	University of Yamanashi
Principal Investigator	FURUICHI Yoshiyuki 山梨大学, 大学院・医学工学総合研究部, 医学研究員 (20467137)
Project Period (FY)	2010 – 2012
Project Status	Completed (Fiscal Year 2012)
Budget Amount *help	¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000) Fiscal Year 2012: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000) Fiscal Year 2011: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000) Fiscal Year 2010: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords	11q23 転座型 ALL / 微少残存病変(MRD) / FLT3-ligand(FL) / TGF-beta1 / 骨髄ストローマ細胞 / FOXO / 11q23転座型ALL / 微少残存病変（MRD） / FLT3/FLシステム
Research Abstract	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.