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Blood. 2014 May 15;123(20):3116-27. doi: 10.1182/blood-2013-05-499970. Epub 2014 Apr 3.

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

Author information

1
Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom;
2
Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom; Khyber Medical University, Hayatabad, Peshawar, Pakistan;
3
Bristol Institute for Transfusion Sciences, National Health Service Blood and Transplant, Filton, Bristol, United Kingdom;
4
Bristol Institute for Transfusion Sciences, National Health Service Blood and Transplant, Filton, Bristol, United Kingdom; School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom;
5
Endocrinology Unit, Centre for Cardiovascular Sciences, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom;
6
Department of Paediatric Haematology, Royal Hospital for Sick Children, Edinburgh, United Kingdom; and.
7
Department of Paediatric Haematology, Royal Hospital for Sick Children, Yorkhill, Glasgow, United Kingdom.
8
Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom; Department of Paediatric Haematology, Royal Hospital for Sick Children, Yorkhill, Glasgow, United Kingdom.

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.

PMID:
24700781
DOI:
10.1182/blood-2013-05-499970
[Indexed for MEDLINE]
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