title: Prognostic implications of mutations and expression of the Wilms tumor 1 (WT1) gene in adult acute T-lymphoblastic leukemia.
abstract: BACKGROUND
  The role of the Wilms tumor 1 gene (WT1) in acute leukemias has been underscored by mutations found in acute myeloid leukemia identifying patients with inferior survival. Furthermore, aberrant expression of WT1 in acute myeloid leukemia was associated with an increased risk of relapse. No larger studies have performed a combined approach including WT1 mutation and expression analyses in acute T-lymphoblastic leukemia.
  
  
  METHODS
  We analyzed the WT1 mutations and the expression status in a total of 252 consecutive adult patients with newly diagnosed T-lymphoblastic leukemia, who were registered on the GMALL 06/99 and 07/03 protocols and had sufficient material available. The GMALL protocols included intensive chemotherapy as well as stem cell transplantation according to a risk-based model with indication for stem cell transplantation in first complete remission for early and mature T-lymphoblastic leukemia patients; patients with thymic T-lymphoblastic leukemia were allocated to a standard risk group and treated with intensive chemotherapy.
  
  
  RESULTS
  Twenty of the 238 patients analyzed had WT1 mutations (WT1mut) in exon 7. WT1mut cases were characterized by immature features such as an early immunophenotype and higher WT1 expression. In thymic T-lymphoblastic leukemia, WT1mut patients had an inferior relapse-free survival compared to WT1 wild-type patients. T-lymphoblastic leukemia patients with aberrant WT1 expression (high or negative) showed a higher relapse rate and an inferior outcome compared to patients with intermediate WT1 expression. In the standard risk group of thymic T-lymphoblastic leukemia, aberrant WT1 expression was predictive for an inferior relapse-free survival as compared to patients with intermediate expression. In multivariate analysis, WT1 expression was of independent prognostic significance for relapse-free survival.
  
  
  CONCLUSIONS
  WT1 mutations were associated with an inferior relapse-free survival in standard risk thymic T-lymphoblastic leukemia patients. Moreover, altered expression associated with inferior outcome also suggests a role of WT1 in T-lymphoblastic leukemia and the potential use of molecularly-based treatment stratification to improve outcome.
authors.affiliation: Department of Hematology and Oncology, Charité, University Hospital Berlin, Campus Benjamin Franklin, Hindenburgdamm 30 12203 Berlin, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Heesch
authors.forename: Nicola
authors.initials: N
authors.lastname: Goekbuget
authors.forename: Andrea
authors.initials: A
authors.lastname: Stroux
authors.forename: Jutta Ortiz
authors.initials: JO
authors.lastname: Tanchez
authors.forename: Cornelia
authors.initials: C
authors.lastname: Schlee
authors.forename: Thomas
authors.initials: T
authors.lastname: Burmeister
authors.forename: Stefan
authors.initials: S
authors.lastname: Schwartz
authors.forename: Olga
authors.initials: O
authors.lastname: Blau
authors.forename: Ulrich
authors.initials: U
authors.lastname: Keilholz
authors.forename: Antonia
authors.initials: A
authors.lastname: Busse
authors.forename: Dieter
authors.initials: D
authors.lastname: Hoelzer
authors.forename: Eckhard
authors.initials: E
authors.lastname: Thiel
authors.forename: Wolf-Karsten
authors.initials: WK
authors.lastname: Hofmann
authors.forename: Claudia D
authors.initials: CD
authors.lastname: Baldus
mesh_terms: D000293:Adolescent; D000328:Adult; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016162:Genes, Wilms Tumor / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D015996:Survival Rate / Q000639:trends; D055815:Young Adult