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 language | English |
---|---|
Pages (from-to) | 3116-27 |
Number of pages | 12 |
Journal | Blood |
Volume | 123 |
Issue number | 20 |
DOIs | |
Publication status | Published - 15 May 2014 |
Keywords / Materials (for Non-textual outputs)
- 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