title: Identification of hepatic niche harboring human acute lymphoblastic leukemic cells via the SDF-1/CXCR4 axis.
abstract: In acute lymphoblastic leukemia (ALL) patients, the bone marrow niche is widely known to be an important element of treatment response and relapse. Furthermore, a characteristic liver pathology observed in ALL patients implies that the hepatic microenvironment provides an extramedullary niche for leukemic cells. However, it remains unclear whether the liver actually provides a specific niche. The mechanism underlying this pathology is also poorly understood. Here, to answer these questions, we reconstituted the histopathology of leukemic liver by using patients-derived primary ALL cells into NOD/SCID/Yc (null) mice. The liver pathology in this model was similar to that observed in the patients. By using this model, we clearly demonstrated that bile duct epithelial cells form a hepatic niche that supports infiltration and proliferation of ALL cells in the liver. Furthermore, we showed that functions of the niche are maintained by the SDF-1/CXCR4 axis, proposing a novel therapeutic approach targeting the extramedullary niche by inhibition of the SDF-1/CXCR4 axis. In conclusion, we demonstrated that the liver dissemination of leukemia is not due to nonselective infiltration, but rather systematic invasion and proliferation of leukemic cells in hepatic niche. Although the contribution of SDF-1/CXCR4 axis is reported in some cancer cells or leukemic niches such as bone marrow, we demonstrated that this axis works even in the extramedullary niche of leukemic cells. Our findings form the basis for therapeutic approaches that target the extramedullary niche by inhibiting the SDF-1/CXCR4 axis.
authors: Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
authors: Itaru
authors: I
authors: Kato
authors: Akira
authors: A
authors: Niwa
authors: Toshio
authors: T
authors: Heike
authors: Hisanori
authors: H
authors: Fujino
authors: Megumu K
authors: MK
authors: Saito
authors: Katsutsugu
authors: K
authors: Umeda
authors: Hidefumi
authors: H
authors: Hiramatsu
authors: Mamoru
authors: M
authors: Ito
authors: Makiko
authors: M
authors: Morita
authors: Yoko
authors: Y
authors: Nishinaka
authors: Souichi
authors: S
authors: Adachi
authors: Fumihiko
authors: F
authors: Ishikawa
authors: Tatsutoshi
authors: T
authors: Nakahata
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology; D001596:Benzylamines; D015153:Blotting, Western; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D000080027:Cyclams; D005260:Female; D005434:Flow Cytometry; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D007223:Infant; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D019380:Anti-HIV Agents; D001596:Benzylamines; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; C088327:plerixafor