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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)

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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, Vol. 125, No. 5, 29.01.2015, p. 820-30.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Krause, S, Pfeiffer, C, Strube, S, Alsadeq, A, Fedders, H, Vokuhl, C, Loges, S, Waizenegger, J, Ben-Batalla, I, Cario, G, Möricke, A, Stanulla, M, Schrappe, M & Schewe, DM 2015, 'Mer tyrosine kinase promotes the survival of t(1;19)-positive acute lymphoblastic leukemia (ALL) in the central nervous system (CNS)', BLOOD, vol. 125, no. 5, pp. 820-30. https://doi.org/10.1182/blood-2014-06-583062

APA

Krause, S., Pfeiffer, C., Strube, S., Alsadeq, A., Fedders, H., Vokuhl, C., Loges, S., Waizenegger, J., Ben-Batalla, I., Cario, G., Möricke, A., Stanulla, M., Schrappe, M., & Schewe, D. M. (2015). Mer tyrosine kinase promotes the survival of t(1;19)-positive acute lymphoblastic leukemia (ALL) in the central nervous system (CNS). BLOOD, 125(5), 820-30. https://doi.org/10.1182/blood-2014-06-583062

Vancouver

Krause S, Pfeiffer C, Strube S, Alsadeq A, Fedders H, Vokuhl C et al. Mer tyrosine kinase promotes the survival of t(1;19)-positive acute lymphoblastic leukemia (ALL) in the central nervous system (CNS). BLOOD. 2015 Jan 29;125(5):820-30. https://doi.org/10.1182/blood-2014-06-583062

Bibtex

@article{b200addb3df14d67b7aacb4f160ac486,
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.",
keywords = "Animals, Antimetabolites, Antineoplastic, Astrocytes, Case-Control Studies, Cell Survival, Central Nervous System, Child, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 19, Coculture Techniques, Female, Galectin 3, Gene Expression Regulation, Leukemic, Glioma, Humans, Methotrexate, Mice, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Primary Cell Culture, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Pyrazoles, Pyrimidines, RNA, Small Interfering, Receptor Protein-Tyrosine Kinases, Signal Transduction, Translocation, Genetic, Tumor Cells, Cultured",
author = "Sarah Krause and Christian Pfeiffer and Susanne Strube and Ameera Alsadeq and Henning Fedders and Christian Vokuhl and Sonja Loges and Jonas Waizenegger and Isabel Ben-Batalla and Gunnar Cario and Anja M{\"o}ricke and Martin Stanulla and Martin Schrappe and Schewe, {Denis M}",
note = "{\textcopyright} 2015 by The American Society of Hematology.",
year = "2015",
month = jan,
day = "29",
doi = "10.1182/blood-2014-06-583062",
language = "English",
volume = "125",
pages = "820--30",
journal = "BLOOD",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "5",

}

RIS

TY - JOUR

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 -