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

  1. Lookup NU author(s)
  2. Marian Case
  3. Elizabeth Matheson
  4. Lynne Minto
  5. Dr Nicholas Bown
  6. Professor Simon Bailey
  7. Professor Josef Vormoor
  8. Professor Andy Hall
  9. Dr Julie Irving
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
JournalCancer Research
Year2008
Volume68
Issue16
Pages6803-6809
ISSN (print)0008-5472
ISSN (electronic)1538-7445
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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.
PublisherAmerican Association for Cancer Research
URLhttp://dx.doi.org/10.1158/0008-5472.CAN-08-0101
DOI10.1158/0008-5472.CAN-08-0101
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