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Mutation of Genes Affecting the RAS Pathway Is Common in Childhood Acute Lymphoblastic Leukemia

¹ Northern Institute for Cancer Research; ² Institute of Human Genetics; ³ Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom; ⁴ University Sains Malaysia, Penang, Malaysia; and ⁵ University of Southampton, Southampton, United Kingdom

Requests for reprints: Julie Anne Elizabeth Irving, Northern Institute for Cancer Research, Paul O'Gorman Building, Framlington Place, Newcastle upon Tyne, Tyne and Wear, United Kingdom. Phone: 44-191-246-4369; Fax: 44-191-246-4301; E-mail: j.a.e.irving{at}ncl.ac.uk.

Key Words: Childhood acute lymphoblastic leukemia • RAS • BRAF • PTPN11 • MEK/ERK inhibitors

Deregulation of the RAS-RAF-mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK signaling cascade is often caused by somatic mutations in genes encoding proteins which influence the activity of this pathway and include NRAS, KRAS2, FLT3, PTPN11, and BRAF. We report the first comprehensive mutational screen of key exons of these genes in a large cohort of unselected acute lymphoblastic leukemia (ALL) cases at diagnosis (n = 86) and in a more selected cohort at disease recurrence (n = 47) using the sensitive method of denaturing high-performance liquid chromatography. We show that somatic mutations that deregulate the pathway constitute one of the most common genetic aberrations in childhood ALL (cALL), being found in 35% of diagnostic and 25% of relapse samples. In matched presentation/relapse pairs, mutations predominating at relapse could be shown to be present at very low levels at diagnosis using allele-specific PCR, thus implicating the mutated clone in disease progression. Importantly, in primary samples, we show that mutations are associated with activated ERK and differential cytotoxicity to MEK-ERK inhibitors was shown for some patients. Inhibitors of the pathway, which are currently undergoing clinical trial, may be a novel therapeutic option for cALL, particularly at relapse. [Cancer Res 2008;68(16):6803–9]