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

• Published in: Blood Vol. 123; no. 20; pp. 3116 - 3127
• Main Authors: Williams, Mark T.S., Yousafzai, Yasar, Cox, Charlotte, Blair, Allison, Carmody, Ruaidhrí, Sai, Shuji, Chapman, Karen E., McAndrew, Rachel, Thomas, Angela, Spence, Alison, Gibson, Brenda, Graham, Gerard J., Halsey, Christina
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.05.2014
• Subjects: Animals; Cell Line, Tumor; Cell Proliferation - drug effects; Central Nervous System - immunology; Central Nervous System - metabolism; Central Nervous System - pathology; Gene Expression Regulation, Neoplastic; Humans; Interleukin-15 - genetics; Interleukin-15 - immunology; Membrane Glycoproteins - genetics; Mice; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - immunology; NF-kappa B - antagonists & inhibitors; NF-kappa B - immunology; Phosphatidylinositol 3-Kinases - immunology; Phosphoinositide-3 Kinase Inhibitors; Plasminogen Activator Inhibitor 1 - genetics; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - immunology; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Receptors, CXCR3 - genetics; Signal Transduction; STAT5 Transcription Factor - antagonists & inhibitors; STAT5 Transcription Factor - immunology; Up-Regulation
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2013-05-499970

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. •IL-15 has been implicated in CNS disease and leukemogenesis, but the biological mechanisms are unknown.•IL-15 increases pre-B ALL growth and upregulates CNS homing molecules, and MEK/ERK, PI3K, and NF-κB inhibitors block IL-15 growth effects.