title: Mer tyrosine kinase promotes the survival of t(1;19)-positive acute lymphoblastic leukemia (ALL) in the central nervous system (CNS).
abstract: Patients with t(1;19)-positive acute lymphoblastic leukemia (ALL) are prone to central nervous system (CNS) relapses, and expression of the TAM (Tyro3, Axl, and Mer) receptor Mer is upregulated in these leukemias. We examined the functional role of Mer in the CNS in preclinical models and performed correlative studies in 64 t(1;19)-positive and 93 control pediatric ALL patients. ALL cells were analyzed in coculture with human glioma cells and normal rat astrocytes: CNS coculture caused quiescence and protection from methotrexate toxicity in Mer(high) ALL cell lines, which was antagonized by short hairpin RNA-mediated knockdown of Mer. Mer expression was upregulated, prosurvival Akt and mitogen-activated protein kinase signaling were activated, and secretion of the Mer ligand Galectin-3 was stimulated. Mer(high) t(1;19) primary cells caused CNS involvement to a larger extent in murine xenografts than in their Mer(low) counterparts. Leukemic cells from Mer(high) xenografts showed enhanced survival in coculture. Treatment of Mer(high) patient cells with the Mer-specific inhibitor UNC-569 in vivo delayed leukemia onset, reduced CNS infiltration, and prolonged survival of mice. Finally, a correlation between high Mer expression and CNS positivity upon initial diagnosis was observed in t(1;19) patients. Our data provide evidence that Mer is associated with survival in the CNS in t(1;19)-positive ALL, suggesting a role as a diagnostic marker and therapeutic target.
authors.affiliation: Department of General Pediatrics, Acute Lymphoblastic Leukemia-Berlin-Frankfurt-Münster Study Group, and.
authors.forename: Sarah
authors.initials: S
authors.lastname: Krause
authors.affiliation: Department of General Pediatrics, Acute Lymphoblastic Leukemia-Berlin-Frankfurt-Münster Study Group, and.
authors.forename: Christian
authors.initials: C
authors.lastname: Pfeiffer
authors.affiliation: Department of General Pediatrics, Acute Lymphoblastic Leukemia-Berlin-Frankfurt-Münster Study Group, and.
authors.forename: Susanne
authors.initials: S
authors.lastname: Strube
authors.affiliation: Department of General Pediatrics, Acute Lymphoblastic Leukemia-Berlin-Frankfurt-Münster Study Group, and.
authors.forename: Ameera
authors.initials: A
authors.lastname: Alsadeq
authors.affiliation: Department of General Pediatrics, Acute Lymphoblastic Leukemia-Berlin-Frankfurt-Münster Study Group, and.
authors.forename: Henning
authors.initials: H
authors.lastname: Fedders
authors.affiliation: Department of Children's Pathology, University Hospital Schleswig-Holstein, Kiel, Germany; and.
authors.forename: Christian
authors.initials: C
authors.lastname: Vokuhl
authors.affiliation: II. Medical Clinic and Institute of Tumor Biology, University Hospital Eppendorf, Hamburg, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Loges
authors.affiliation: II. Medical Clinic and Institute of Tumor Biology, University Hospital Eppendorf, Hamburg, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Waizenegger
authors.affiliation: II. Medical Clinic and Institute of Tumor Biology, University Hospital Eppendorf, Hamburg, Germany.
authors.forename: Isabel
authors.initials: I
authors.lastname: Ben-Batalla
authors.affiliation: Department of General Pediatrics, Acute Lymphoblastic Leukemia-Berlin-Frankfurt-Münster Study Group, and.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Cario
authors.affiliation: Department of General Pediatrics, Acute Lymphoblastic Leukemia-Berlin-Frankfurt-Münster Study Group, and.
authors.forename: Anja
authors.initials: A
authors.lastname: Möricke
authors.affiliation: Department of General Pediatrics, Acute Lymphoblastic Leukemia-Berlin-Frankfurt-Münster Study Group, and.
authors.forename: Martin
authors.initials: M
authors.lastname: Stanulla
authors.affiliation: Department of General Pediatrics, Acute Lymphoblastic Leukemia-Berlin-Frankfurt-Münster Study Group, and.
authors.forename: Martin
authors.initials: M
authors.lastname: Schrappe
authors.affiliation: Department of General Pediatrics, Acute Lymphoblastic Leukemia-Berlin-Frankfurt-Münster Study Group, and.
authors.forename: Denis M
authors.initials: DM
authors.lastname: Schewe
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001798:Blood Proteins; D016022:Case-Control Studies; D002470:Cell Survival; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002648:Child; D002878:Chromosomes, Human, Pair 1; D002888:Chromosomes, Human, Pair 19; D018920:Coculture Techniques; D005260:Female; D037502:Galectin 3 / Q000235:genetics / Q000378:metabolism; D037161:Galectins; D015973:Gene Expression Regulation, Leukemic; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured; D000076202:c-Mer Tyrosine Kinase
chemical_list: D000964:Antimetabolites, Antineoplastic; D001798:Blood Proteins; D037502:Galectin 3; D037161:Galectins; C428445:LGALS3 protein, human; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D034741:RNA, Small Interfering; C000589254:UNC569; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase; D051057:Proto-Oncogene Proteins c-akt; D008727:Methotrexate