Publication:

Mutation of genes affecting the RAS pathway is common in childhood acute lymphoblastic leukemia (2008)

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

    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.

      • Date: 15-08-2008
      • Journal: Cancer Research
      • Volume: 68
      • Issue: 16
      • Pages: 6803-6809
      • Publisher: American Association for Cancer Research
      • Publication type: Article
      • Bibliographic status: Published

      Keywords: Adolescent Blotting, Western Cell Survival Child Child, Preschool Cohort Studies DNA Mutational Analysis Enzyme Inhibitors/pharmacology Exons/genetics Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors/metabolism Female Genes, ras/*physiology Humans In Situ Hybridization, Fluorescence Infant Male Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors/metabolism Mitogen-Activated Protein Kinases/antagonists & inhibitors/metabolism Mutation/*genetics Neoplasm Recurrence, Local/*genetics/pathology Peptide Fragments Ploidies Precursor Cell Lymphoblastic Leukemia-Lymphoma/*genetics/pathology Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics Proto-Oncogene Proteins/*genetics Proto-Oncogene Proteins B-raf/genetics Remission Induction *Signal Transduction Tumor Cells, Cultured fms-Like Tyrosine Kinase 3/genetics ras Proteins/*genetics

      Staff

      Professor Andy Hall
      Director, NICR

      Dr Julie Irving
      Reader in Experimental Haematology