title: A CXCR4 antagonist leads to tumor suppression by activation of immune cells in a leukemia-induced microenvironment.
abstract: The bone marrow microenvironment (BMM) provides a protective niche that supports growth and survival of normal and leukemic hematopoietic stem cells. The SDF-1/CXCR4 interaction is critical for regulation of homing to and retention of hematopoietic cells in the bone marrow (BM), which leads to increased chemoresistance. SDF-1/CXCR4 plays pivotal roles in cross-interactions between blasts and the BMM to prevent retention and mobilization of leukemic cells, as well as in normal hematopoiesis including the development of immune cells. We show that the CXCR4 antagonist, plerixafor, decreased the level of CXCR4 expression and inhibited SDF-1-induced migration of leukemic cells. Further, the inhibition of the interaction between leukemic cells and the BMM by the plerixafor enhanced cytotoxic activity of immune cells as a result of increased susceptibility of leukemic cells to chemotherapeutic agents such as cytosine arabinoside (Ara-C) in a mouse model of acute myeloid leukemia (AML), suggesting biological effects of the BMM through immune cell activation. Because alterations in the BMM promote retention and survival of leukemic cells, targeting the niche is regarded as an advanced strategy to eradicate drug-resistant leukemic blasts. This study demonstrates that the effects of CXCR4 inhibition on blast suppression and immune cell function in the tumor microenvironment and chemotherapy with plerixafor represents an advanced therapeutic strategy of targeting the leukemic niche.
authors.affiliation: Cancer Research Institute, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: A-Reum
authors.initials: AR
authors.lastname: Han
authors.affiliation: Cancer Research Institute, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Ji Yoon
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Cancer Research Institute, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Hee-Je
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Hematology, Catholic Blood and Marrow Transplantation Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Woo-Sung
authors.initials: WS
authors.lastname: Min
authors.affiliation: Cancer Research Institute, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Gyeongsin
authors.initials: G
authors.lastname: Park
authors.affiliation: Cancer Research Institute, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Se-Hoon
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001596:Benzylamines; D001854:Bone Marrow Cells / Q000276:immunology / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D054377:Chemokine CXCL12 / Q000235:genetics* / Q000378:metabolism; D000080027:Cyclams; D003561:Cytarabine / Q000008:administration & dosage; D005260:Female; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000276:immunology; D006571:Heterocyclic Compounds / Q000008:administration & dosage; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000276:immunology* / Q000473:pathology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D001596:Benzylamines; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D003561:Cytarabine; C088327:plerixafor