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. doi: 10.1182/blood-2014-06-583062. Epub 2014 Nov 26.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / pharmacology
  • Astrocytes / cytology
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Blood Proteins
  • Case-Control Studies
  • Cell Survival
  • Central Nervous System / drug effects
  • Central Nervous System / metabolism*
  • Central Nervous System / pathology
  • Child
  • Chromosomes, Human, Pair 1
  • Chromosomes, Human, Pair 19
  • Coculture Techniques
  • Female
  • Galectin 3 / genetics
  • Galectin 3 / metabolism
  • Galectins
  • Gene Expression Regulation, Leukemic*
  • Glioma / genetics
  • Glioma / metabolism
  • Glioma / pathology
  • Humans
  • Methotrexate / pharmacology
  • Mice
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Primary Cell Culture
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyrazoles / therapeutic use*
  • Pyrimidines / therapeutic use*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Signal Transduction
  • Translocation, Genetic
  • Tumor Cells, Cultured
  • c-Mer Tyrosine Kinase

Substances

  • Antimetabolites, Antineoplastic
  • Blood Proteins
  • Galectin 3
  • Galectins
  • LGALS3 protein, human
  • Proto-Oncogene Proteins
  • Pyrazoles
  • Pyrimidines
  • RNA, Small Interfering
  • UNC569
  • MERTK protein, human
  • Receptor Protein-Tyrosine Kinases
  • c-Mer Tyrosine Kinase
  • Proto-Oncogene Proteins c-akt
  • Methotrexate