Interleukin-15 enhances cellular proliferation and upregulates CNS homing molecules in pre-B acute lymphoblastic leukemia

Mark T S Williams, Yasar Yousafzai, Charlotte Cox, Allison Blair, Ruaidhrí Carmody, Shuji Sai, Karen E Chapman, Rachel McAndrew, Angela Thomas, Alison Spence, Brenda Gibson, Gerard J Graham, Christina Halsey

Research output: Contribution to journalArticlepeer-review

Abstract

Genome-wide association studies have consistently implicated the interleukin-15 (IL-15) gene in acute lymphoblastic leukemia (ALL) biology, including associations with disease susceptibility, and increased risk of central nervous system (CNS) involvement. However, whether pre-B ALL blasts directly respond to IL-15 is unknown. Here, we show that most pre-B ALL primary samples and cell lines express IL-15 and components of its receptor and that primary pre-B ALL cells show increased growth in culture in response to IL-15. Investigation of mechanisms of action using IL-15-responsive SD-1 cells shows this growth advantage is maximal under low-serum conditions, mimicking those found in cerebrospinal fluid. IL-15 also upregulates PSGL-1 and CXCR3, molecules associated with CNS trafficking. Investigation of downstream signaling pathways indicates that IL-15 induces signal transducer and activator of transcription 5 (STAT5), extracellular signal-regulated kinase (ERK) 1/2, and to a lesser extent phosphatidylinositol 3-kinase (PI3K) and nuclear factor κB (NF-κB) phosphorylation. The IL-15-mediated growth advantage is abolished by mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK), PI3K, and NF-κB inhibitors but preserved in the presence of STAT5 inhibition. Together, these observations provide a mechanistic link between increased levels of IL-15 expression and leukemogenesis, high-risk disease, and CNS relapse and suggest potential therapeutic targets.

Original languageEnglish
Pages (from-to)3116-27
Number of pages12
JournalBlood
Volume123
Issue number20
DOIs
Publication statusPublished - 15 May 2014

Keywords

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Central Nervous System
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Interleukin-15
  • Membrane Glycoproteins
  • Mice
  • Mitogen-Activated Protein Kinases
  • NF-kappa B
  • Phosphatidylinositol 3-Kinases
  • Plasminogen Activator Inhibitor 1
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
  • Receptors, CXCR3
  • STAT5 Transcription Factor
  • Signal Transduction
  • Up-Regulation

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