Mer tyrosine kinase promotes the survival of t(1;19)-positive acute lymphoblastic leukemia (ALL) in the central nervous system (CNS)
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Mer tyrosine kinase promotes the survival of t(1;19)-positive acute lymphoblastic leukemia (ALL) in the central nervous system (CNS). / Krause, Sarah; Pfeiffer, Christian; Strube, Susanne; Alsadeq, Ameera; Fedders, Henning; Vokuhl, Christian; Loges, Sonja; Waizenegger, Jonas; Ben-Batalla, Isabel; Cario, Gunnar; Möricke, Anja; Stanulla, Martin; Schrappe, Martin; Schewe, Denis M.
in: BLOOD, Jahrgang 125, Nr. 5, 29.01.2015, S. 820-30.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Mer tyrosine kinase promotes the survival of t(1;19)-positive acute lymphoblastic leukemia (ALL) in the central nervous system (CNS)
AU - Krause, Sarah
AU - Pfeiffer, Christian
AU - Strube, Susanne
AU - Alsadeq, Ameera
AU - Fedders, Henning
AU - Vokuhl, Christian
AU - Loges, Sonja
AU - Waizenegger, Jonas
AU - Ben-Batalla, Isabel
AU - Cario, Gunnar
AU - Möricke, Anja
AU - Stanulla, Martin
AU - Schrappe, Martin
AU - Schewe, Denis M
N1 - © 2015 by The American Society of Hematology.
PY - 2015/1/29
Y1 - 2015/1/29
N2 - 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.
AB - 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.
KW - Animals
KW - Antimetabolites, Antineoplastic
KW - Astrocytes
KW - Case-Control Studies
KW - Cell Survival
KW - Central Nervous System
KW - Child
KW - Chromosomes, Human, Pair 1
KW - Chromosomes, Human, Pair 19
KW - Coculture Techniques
KW - Female
KW - Galectin 3
KW - Gene Expression Regulation, Leukemic
KW - Glioma
KW - Humans
KW - Methotrexate
KW - Mice
KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma
KW - Primary Cell Culture
KW - Proto-Oncogene Proteins
KW - Proto-Oncogene Proteins c-akt
KW - Pyrazoles
KW - Pyrimidines
KW - RNA, Small Interfering
KW - Receptor Protein-Tyrosine Kinases
KW - Signal Transduction
KW - Translocation, Genetic
KW - Tumor Cells, Cultured
U2 - 10.1182/blood-2014-06-583062
DO - 10.1182/blood-2014-06-583062
M3 - SCORING: Journal article
C2 - 25428221
VL - 125
SP - 820
EP - 830
JO - BLOOD
JF - BLOOD
SN - 0006-4971
IS - 5
ER -