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

Williams, M. T.S. et al. (2014) Interleukin-15 enhances cellular proliferation and up-regulates CNS homing molecules in pre-B acute lymphoblastic leukemia. Blood, 123(20), pp. 3116-3127. (doi:10.1182/blood-2013-05-499970) (PMID:24700781)

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Publisher's URL: http://dx.doi.org/10.1182/blood-2013-05-499970

Abstract

Genome-wide association studies and transcriptomics have consistently implicated the interleukin-15 (IL-15) gene in acute lymphoblastic leukemia (ALL) biology, including associations with disease susceptibility, resistance to initial therapy and increased risk of mediastinal and central nervous system (CNS) involvement. However, whether pre-B ALL blasts directly respond to IL-15 is currently unknown. Here we show that the majority of pre-B ALL primary samples and cell lines express IL-15 and all 3 components of its heterotrimeric receptor and that primary pre-B ALL cells show increased growth in culture in response to IL-15. Investigation of mechanisms of action using highly IL-15 responsive SD-1 cells shows this growth advantage is maximal under low serum conditions, mimicking those found in cerebrospinal fluid. Addition of IL-15 also up-regulates PSGL-1 and CXCR3, molecules associated with lymph-node and CNS trafficking. Investigation of downstream signalling pathways indicates that IL-15 induces STAT5, ERK1/2 and to a lesser extent PI3K and NFκB phosphorylation. The IL-15 mediated growth advantage is abolished by MEK/ERK, PI3K and NFκB inhibitors, but preserved in the presence of STAT5 inhibition. Together these observations provide a plausible mechanistic link between increased levels of IL-15 expression and leukemogenesis, high-risk disease, mediastinal involvement and CNS relapse and suggest potential therapeutic targets.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Carmody, Dr Ruaidhri and Halsey, Dr Chris and Williams, Dr Mark and Gibson, Professor Brenda and Graham, Professor Gerard
Authors: Williams, M. T.S., Yousafzai, Y., Cox, C., Blair, A., Carmody, R., Sai, S., Chapman, K. E., McAndrew, R., Thomas, A., Spence, A., Gibson, B., Graham, G., and Halsey, C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Blood
Publisher:American Society of Hematology
ISSN:0006-4971
ISSN (Online):1528-0020
Copyright Holders:Copyright © 2014 American Society of Hematology
First Published:First published in Blood 123(20):3116-3127
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher.

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
530441An investigation into the molecular basis for B lineage acute lymphoblastic leukaemia migration to extramedullary sites.Christina HalseyKay Kendal Leukaemia Fund (KAY-KENDAL)KKL454III -IMMUNOLOGY
533471A Molecular Characterisation of Central Nervous System LeukaemiaChristina HalseyScottish Executive Health Department (SEHHD-CSO)SCD/08III -IMMUNOLOGY
514422Regulation of the adaptive immune response by chemokine scavenging receptorsGerard GrahamMedical Research Council (MRC)G0901113III -IMMUNOLOGY