Interleukin-15 enhances cellular proliferation and upregulates CNS homing molecules in pre-B acute lymphoblastic leukemia.
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.
Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom;
Mark T S
MT
Williams
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;
Yasar
Y
Yousafzai
Bristol Institute for Transfusion Sciences, National Health Service Blood and Transplant, Filton, Bristol, United Kingdom;
Charlotte
C
Cox
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;
Allison
A
Blair
Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom;
Ruaidhrí
R
Carmody
Endocrinology Unit, Centre for Cardiovascular Sciences, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom;
Shuji
S
Sai
Endocrinology Unit, Centre for Cardiovascular Sciences, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom;
Karen E
KE
Chapman
Department of Paediatric Haematology, Royal Hospital for Sick Children, Edinburgh, United Kingdom; and.
Rachel
R
McAndrew
Department of Paediatric Haematology, Royal Hospital for Sick Children, Edinburgh, United Kingdom; and.
Angela
A
Thomas
Department of Paediatric Haematology, Royal Hospital for Sick Children, Yorkhill, Glasgow, United Kingdom.
Alison
A
Spence
Department of Paediatric Haematology, Royal Hospital for Sick Children, Yorkhill, Glasgow, United Kingdom.
Brenda
B
Gibson
Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom;
Gerard J
GJ
Graham
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.
Christina
C
Halsey
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002490:Central Nervous System / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019409:Interleukin-15 / Q000235:genetics / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000276:immunology*; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D054367:Receptors, CXCR3 / Q000235:genetics; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors / Q000276:immunology; D015398:Signal Transduction; D015854:Up-Regulation
D019409:Interleukin-15; D008562:Membrane Glycoproteins; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017395:Plasminogen Activator Inhibitor 1; D054367:Receptors, CXCR3; D050799:STAT5 Transcription Factor; C084882:P-selectin ligand protein