title: Chemokines and relapses in childhood acute lymphoblastic leukemia: A role in migration and in resistance to antileukemic drugs.
abstract: We studied whether chemokines may have a role in relapses in childhood acute lymphoblastic leukemia (ALL). We compared the levels of chemokine receptors in marrow samples from 82 children with ALL at diagnosis versus 15 at relapses, and quantified the levels of chemokines in central system fluid (CSF) samples. The functional role of specific chemokines was studied in vitro and in vivo. The expression of some chemokine receptors was upregulated upon leukemic relapse, both in B- and in T-ALL, and in cases of medullary and extramedullary involvement. CXCL10 induced chemotaxis in leukemic cell lines and in primary leukemic cells, depending upon the levels of CXCR3 expression. CXCL10 specifically diminished chemotherapy-induced apoptosis on ALL cells expressing CXCR3, partially inhibiting caspase activation and maintaining the levels of the antiapoptotic protein Bcl-2. Finally, immunodeficient mice engrafted with CXCR3-expressing human leukemic cells showed decreased infiltration of marrow, spleen, and CNS after receiving a CXCR3-antagonist molecule. CXCR3 signaling in ALL may have a dual function: chemotactic for the localisation of leukemic blasts in specific niches, and it may also confer resistance to chemotherapy, enhancing the chances for relapses.
authors.affiliation: Servicio de Oncohematología, Hospital Universitario Niño Jesús, Madrid, Spain.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Gómez
authors.affiliation: Servicio de Oncohematología, Hospital Universitario Niño Jesús, Madrid, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Martínez
authors.affiliation: Facultad de Ciencias, Universidad de Extremadura, Badajoz, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: González
authors.affiliation: Servicio de Oncohematología, Hospital Universitario Niño Jesús, Madrid, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Luque
authors.affiliation: Servicio de Oncohematología, Hospital Universitario Niño Jesús, Madrid, Spain.
authors.forename: Gustavo J
authors.initials: GJ
authors.lastname: Melen
authors.affiliation: Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Martínez
authors.affiliation: Instituto de Salud Carlos III, Majadahonda, Spain.
authors.forename: Sonsoles
authors.initials: S
authors.lastname: Hortelano
authors.affiliation: Servicio de Oncohematología, Hospital Universitario Niño Jesús, Madrid, Spain.
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Lassaletta
authors.affiliation: Servicio de Oncohematología, Hospital Universitario Niño Jesús, Madrid, Spain.
authors.forename: Luís
authors.initials: L
authors.lastname: Madero
authors.affiliation: Servicio de Oncohematología, Hospital Universitario Niño Jesús, Madrid, Spain. Electronic address: manuel.ramirez@salud.madrid.org.
authors.forename: Manuel
authors.initials: M
authors.lastname: Ramírez
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018925:Chemokines / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte; D002648:Child; D019008:Drug Resistance, Neoplasm; D006801:Humans; D051379:Mice; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D019707:Receptors, Chemokine / Q000378:metabolism*; D012008:Recurrence
chemical_list: D000970:Antineoplastic Agents; D018925:Chemokines; D019707:Receptors, Chemokine
keywords: Acute lymphoblastic leukemia; Chemokine receptors; Chemokines; Relapse