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Mutation of genes affecting the RAS pathway is common in childhood acute lymphoblastic leukemia

Lookup NU author(s): Marian Case, Elizabeth Matheson, Lynne Minto, Dr Nicholas Bown, Professor Simon Bailey, Professor Josef Vormoor, Emeritus Professor Andy Hall, Professor Julie Irving

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Abstract

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.


Publication metadata

Author(s): Case MC, Matheson E, Minto L, Hassan R, Harrison CJ, Bown NP, Bailey S, Vormoor J, Hall AG, Irving JAE

Publication type: Article

Journal: Cancer Research

Year: 2008

Volume: 68

Issue: 16

Pages: 6803-6809

ISSN (print): 0008-5472

ISSN (electronic): 1538-7445

Publisher: American Association for Cancer Research

URL: http://dx.doi.org/10.1158/0008-5472.CAN-08-0101

DOI: 10.1158/0008-5472.CAN-08-0101


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