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, Professor 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 > School of Infection & Immunity |
| 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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