title: CXCL12-Producing Vascular Endothelial Niches Control Acute T Cell Leukemia Maintenance.
abstract: The role of the microenvironment in T cell acute lymphoblastic leukemia (T-ALL), or any acute leukemia, is poorly understood. Here we demonstrate that T-ALL cells are in direct, stable contact with CXCL12-producing bone marrow stroma. Cxcl12 deletion from vascular endothelial, but not perivascular, cells impeded tumor growth, suggesting a vascular niche for T-ALL. Moreover, genetic targeting of Cxcr4 in murine T-ALL after disease onset led to rapid, sustained disease remission, and CXCR4 antagonism suppressed human T-ALL in primary xenografts. Loss of CXCR4 targeted key T-ALL regulators, including the MYC pathway, and decreased leukemia initiating cell activity in vivo. Our data identify a T-ALL niche and suggest targeting CXCL12/CXCR4 signaling as a powerful therapeutic approach for T-ALL.
authors.affiliation: Skirball Institute of Biomolecular Medicine, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA; Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Pitt
authors.affiliation: Howard Hughes Medical Institute and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA; Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
authors.forename: Anastasia N
authors.initials: AN
authors.lastname: Tikhonova
authors.affiliation: Howard Hughes Medical Institute and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA; Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Hu
authors.affiliation: Howard Hughes Medical Institute and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA; Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Trimarchi
authors.affiliation: Howard Hughes Medical Institute and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA; Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: King
authors.affiliation: Howard Hughes Medical Institute and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA; Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
authors.forename: Yixiao
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Institute for Cancer Genetics, Department of Pathology and Department of Pediatrics, Columbia University, 1130 Saint Nicholas Avenue, New York, NY 10032, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Sanchez-Martin
authors.affiliation: Howard Hughes Medical Institute and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA; Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
authors.forename: Aris
authors.initials: A
authors.lastname: Tsirigos
authors.affiliation: Howard Hughes Medical Institute and Skirball Institute of Biomolecular Medicine, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA.
authors.forename: Dan R
authors.initials: DR
authors.lastname: Littman
authors.affiliation: Institute for Cancer Genetics, Department of Pathology and Department of Pediatrics, Columbia University, 1130 Saint Nicholas Avenue, New York, NY 10032, USA.
authors.forename: Adolfo A
authors.initials: AA
authors.lastname: Ferrando
authors.affiliation: Howard Hughes Medical Institute and Children's Research Institute and Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Morrison
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Forchheimer Building, Room 131, Bronx, NY 10461, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Fooksman
authors.affiliation: Howard Hughes Medical Institute and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA; Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA. Electronic address: iannis.aifantis@nyumc.org.
authors.forename: Iannis
authors.initials: I
authors.lastname: Aifantis
authors.affiliation: Skirball Institute of Biomolecular Medicine, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA; Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA. Electronic address: susan.schwab@med.nyu.edu.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Schwab
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; C503590:N-(1,4,8,11- tetraazacyclotetradecanyl-1,4-phenylenebis(methylene))-2-(aminomethyl)- pyridine; D011725:Pyridines