An investigation into the role of interleukin-15 on the growth and survival of pre-B acute lymphoblastic leukaemia cell lines

Williams, M.T., Graham, G. , Gibson, B. and Halsey, C. (2011) An investigation into the role of interleukin-15 on the growth and survival of pre-B acute lymphoblastic leukaemia cell lines. In: 51st Annual Scientific Meeting of the British Society for Haematology, Brighton, UK, 4-6 April 2011, pp. 1-88. (doi: 10.1111/j.1365-2141.2011.08609.x)

Abstract

The treatment of refractory/resistant and extramedullary disease inchildhood acute lymphoblastic leukemia (ALL) remains problema-tical. A better biological understanding of the factors involved inleukaemic cell growth, migration and survival should aid develop-ment of novel therapeutic approaches. Two independent genome-wide association studies have identified polymorphisms in theinterleukin-15 (IL-15) gene as predictors of 1) leukemia developmentand 2) resistance to initial therapy. In addition, IL-15 mRNA levelshave been shown to predict the likelihood of central nervous system(CNS) relapse in childhood ALL. IL-15 is a cytokine with autocrineand paracrine effects on T and B cell survival. It is also important forleukocyte migration and alters adhesion molecule expression. Thesecharacteristics support a putative role for IL-15 in leukaemic growth,survival and/or cell migration to sites such as the CNS but this is yetto be tested. In this study we aimed to investigate the biologicalimpact of IL-15 on pre-B ALL cells.We compared the gene and protein expression of IL-15 and itshetero-trimeric receptor (IL-15Ra, b and g) in pre-B ALL cell linesusing Taqman low density qPCR arrays and flow cytometry. Wefound variable levels of expression, with high levels of both IL-15 andits receptor seen in cell lines known to be capable of extramedullaryinfiltration. Transmigration assays failed to show any chemotaxistowards IL-15 in IL-15 receptor expressing cell lines. Using MTT, cellgrowth curves and Annexin V assays we showed that addition ofexogenous IL-15 enhanced the growth of cells in vitro whilstneutralization of the IL-15R significantly reduced their growth.Future studies will investigate the effects of IL-15 on response tochemotherapeutic agents.In summary, these results support a potential role for IL-15 inextramedullary disease and strengthen our hypothesis that IL-15 isinvolved in the growth/survival of ALL cell lines. mechanisms of leukaemic cell entry into the CNS should allow betterdetection and monitoring of leukemia and may identify noveltherapeutic targets for resistant disease. We hypothesize thatleukaemic cell dissemination to the CNS is associated with theabnormal expression of molecules governing physiological leukocytetrafficking i.e. chemokine receptors, selectins and integrins.This study compared gene, protein and functional expression ofcandidate trafficking molecules expressed by CNS homing and CNSnon-homing ALL cell lines in vitro. Initial screening for candidategene expression was performed using Taqman low density quanti-tative PCR arrays. Promising candidates were further evaluated byflow cytometry and functional assays. Clear differences were seenbetween the cell lines. CNS homing cells expressed higher levels ofchemokine receptors, integrins and selectins associated withphysiological entry of leukocytes across the blood:CSF barrier. Incontrast, CNS homing cells showed much lower levels of CXCR4expression, with reduced chemotaxis in response to the CXCR4ligand CXCL12. Since functional CXCR4-CXCL12 interactions areknown to be important for retention of cells in the bone marrowmicroenvironment, disruption of this interaction may be a necessarypre-requisite for cell migration to other sites.In conclusion, these studies support our hypothesis that theability of leukemic cells to enter the CNS is governed by theexpression patterns of leukocyte trafficking receptors.

• Item Type: Conference Proceedings
• Additional Information: Published in British Journal of Haematology, Volume 153, Issue Supplement s1, pages 1–88, April 2011.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Halsey, Professor Chris and Williams, Dr Mark and Gibson, Professor Brenda and Graham, Professor Gerard
• Authors: Williams, M.T., Graham, G., Gibson, B., and Halsey, C.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: British Journal of Haematology
• Publisher: Blackwell Publishing
• ISSN: 0007-1048
• ISSN (Online): 1365-2141