title: The tumor suppressor gene hCDC4 is frequently mutated in human T-cell acute lymphoblastic leukemia with functional consequences for Notch signaling.
abstract: Notch signaling is of crucial importance in normal T-cell development and Notch 1 is frequently mutated in T-cell acute lymphoblastic leukemias (T-ALL), leading to aberrantly high Notch signaling. In this report, we determine whether T-ALL mutations occur not only in Notch1 but also in the F-box protein hCdc4 (Sel-10, Ago, or Fbxw7), a negative regulator of Notch1. We show that the hCDC4 gene is mutated in leukemic cells from more than 30% of patients with pediatric T-ALL and derived cell lines. Most hCDC4 mutations found were missense substitutions at critical arginine residues (Arg(465), Arg(479), and Arg(505)) localized in the substrate-binding region of hCdc4. Cells inactivated for hCdc4 and T-ALL cells containing hCDC4 mutations exhibited an increased Notch1 protein half-life, consistent with the proposed role of hCdc4 in ubiquitin-dependent proteolysis of Notch1. Furthermore, restoration of wild-type but not mutant hCdc4 in HCT 116 hCDC4-negative cells led to an increased Notch1 ubiquitylation and decreased Notch1 signaling. These results show that hCdc4 mutations interfere with normal Notch1 regulation in vivo. Finally, we found that mutations in hCDC4 and NOTCH1 can occur in the same cancers and that patients carrying hCDC4 and/or NOTCH1 mutations have a favorable overall survival. Collectively, these data show that mutation of hCDC4 is a frequent event in T-ALL and suggest that hCDC4 mutations and gain-of-function mutations in NOTCH1 might synergize in contributing to the development of pediatric T-ALL leukemogenesis.
authors.affiliation: Department of Oncology/Pathology, Cancer Center Karolinska, Karolinska Sjukhuset, Sweden.
authors.forename: Alena
authors.initials: A
authors.lastname: Malyukova
authors.forename: Takeaki
authors.initials: T
authors.lastname: Dohda
authors.forename: Natalie
authors.initials: N
authors.lastname: von der Lehr
authors.forename: Shahab
authors.initials: S
authors.lastname: Akhoondi
authors.forename: Shahab
authors.initials: S
authors.lastname: Akhondi
authors.forename: Martin
authors.initials: M
authors.lastname: Corcoran
authors.forename: Mats
authors.initials: M
authors.lastname: Heyman
authors.forename: Charles
authors.initials: C
authors.lastname: Spruck
authors.forename: Dan
authors.initials: D
authors.lastname: Grandér
authors.forename: Urban
authors.initials: U
authors.lastname: Lendahl
authors.forename: Olle
authors.initials: O
authors.lastname: Sangfelt
mesh_terms: D001483:Base Sequence; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D004252:DNA Mutational Analysis; D044783:F-Box Proteins / Q000235:genetics* / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics*; D008297:Male; D009154:Mutation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D051881:Receptor, Notch1; D044767:Ubiquitin-Protein Ligases