Association of CNS involvement in childhood acute lymphoblastic leukaemia with cholesterol biosynthesis upregulation. (23rd February 2017)

• Record Type: Journal Article
• Authors: Cousins, Antony F; Olivares, Orianne; Michie, Alison M; Gottlieb, Eyal; Halsey, Christina
• Is Part Of: Lancet. Volume 389(2017)Supplement 1
• Page Start: S35
• Publication Date: 2017-02-23
• Subjects: Medicine -- Periodicals; Medicine -- Periodicals; Medicine; Medicine; Electronic journals; Periodicals; 610.5
• DOI: 10.1016/S0140-6736(17)30431-2
• Languages: English
• ISSNs: 0140-6736

Abstract

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. Funding: William and Elizabeth Davies Foundation, Chief Scientist Office (ETM/374).