Association of CNS Involvement in Childhood Acute Lymphoblastic Leukaemia with Cholesterol Biosynthesis Upregulation

Cousins, A. F., Olivares, O., Michie, A. M. , Gottlieb, E. and Halsey, C. (2017) Association of CNS Involvement in Childhood Acute Lymphoblastic Leukaemia with Cholesterol Biosynthesis Upregulation. Spring Meeting for Clinician Scientists in Training 2017, London, UK, 23 Feb 2017. S35. (doi:10.1016/S0140-6736(17)30431-2)

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Abstract

Background: Acute lymphoblastic leukaemia is the most common childhood cancer. Despite advances in treatment, meningeal-infiltrating CNS disease (found in up to 90% of children if untreated) remains a challenge. Every child with acute lymphoblastic leukaemia receives intensive and toxic treatment targeting CNS disease, yet CNS involvement at relapse is common. We tested our hypothesis that leukaemic cells must adapt metabolically to survive in the nutritionally poor CNS microenvironment. Methods: Human acute lymphoblastic leukaemia cell lines (SEM and REH) were xenografted into immunodeficient (NSG) mice. Leukaemic cells purified from the CNS and spleen underwent RNA-sequencing (NextSeq 500, Illumina, SanDiego, CA, USA). Clinical validity of findings was explored in publicly available microarray datasets (GSE11877/TARGET and GSE60926) with gene set enrichment and pathway analyses. The effect of simvastatin on SEM cells in vitro, and the development of CNS leukaemia in vivo, was investigated. Findings: RNA-sequencing analysis showed upregulation of the cholesterol biosynthesis pathway in CNS compared with that in systemic leukaemia. GSE60926 microarray data confirmed this finding in leukaemic cells from cerebrospinal fluid in children with acute lymphoblastic leukaemia at CNS relapse versus cells from bone marrow at diagnosis and relapse. Analysis of GSE11877/TARGET data showed that upregulation of two or more cholesterol synthesis genes (z-score ≥2) in the bone marrow blasts at diagnosis was associated with an increased rate of CNS relapse (10 [30·3%] of 33 patients with upregulation vs 15 [8·6%] of 174 patients without; log-rank [Mantel-Cox] p<0·0001). In-vitro study showed that disruption of cholesterol synthesis via hydroxymethylglutaryl-CoA reductase inhibition with simvastatin decreased leukaemic cell proliferation and induced apoptosis. Interestingly, oral simvastatin treatment increased CNS leukaemia in male though not female NSG mice (three per group, Student's t test p=0·0004). Interpretation: Our findings suggest that cholesterol metabolism could be important in CNS acute lymphoblastic leukaemia. Cholesterol biosynthesis is upregulated in CNS leukaemia, and a cholesterol gene signature in diagnostic bone marrow predicts CNS relapse. Disruption of cholesterol synthesis is toxic in vitro but not effective in vivo. Therefore, reduced circulating cholesterol might induce a CNS-like phenotype in systemic acute lymphoblastic leukaemia cells, increasing cholesterol synthesis and adaptation for the CNS niche.

Item Type:Conference or Workshop Item
Additional Information:Poster abstract, Spring Meeting for Clinician Scientists in Training 2017. Published in The Lancet, Volume 389, Supplement 1, 23 February 2017, Page S35.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Cousins, Dr Antony and Halsey, Professor Chris and Gottlieb, Professor Eyal and Michie, Dr Alison and Olivares, Miss Orianne
Authors: Cousins, A. F., Olivares, O., Michie, A. M., Gottlieb, E., and Halsey, C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Lancet
Publisher:The Lancet Publishing Group
ISSN:0140-6736
ISSN (Online):1474-547x

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