title: Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia.
abstract: BACKGROUND
  About a fifth of children with acute T-lymphoblastic leukaemia (T-ALL) succumb to the disease, suggesting an unrecognised biological heterogeneity that might contribute to drug resistance. We postulated that T-ALL originating from early T-cell precursors (ETPs), a recently defined subset of thymocytes that retain stem-cell-like features, would respond poorly to lymphoid-cell-directed therapy. We studied leukaemic cells, collected at diagnosis, to identify cases with ETP features and determine their clinical outcome.
  
  
  METHODS
  Leukaemic cells from 239 patients with T-ALL enrolled at St Jude Children's Research Hospital (n=139) and in the Italian national study Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) ALL-2000 (n=100) were assessed by gene-expression profiling, flow cytometry, and single nucleotide polymorphism array analysis. Probabilities of survival and treatment failure were calculated for subgroups considered to have ETP-ALL or typical T-ALL.
  
  
  RESULTS
  30 patients (12.6%) had leukaemic lymphoblasts with an ETP-related gene-expression signature or its associated distinctive immunophenotype (CD1a(-), CD8(-), CD5(weak) with stem-cell or myeloid markers). Cases of ETP-ALL showed increased genomic instability, in terms of number and size of gene lesions, compared with those with typical T-ALL. Patients with this form of leukaemia had high risk of remission failure or haematological relapse (72% [95% CI 40-100] at 10 years vs 10% [4-16] at 10 years for patients with typical T-ALL treated at St Jude Children's Research Hospital; and 57% [25-89] at 2 years vs 14% [6-22] at 2 years for patients treated in the AIEOP trial).
  
  
  CONCLUSIONS
  ETP-ALL is a distinct, previously unrecognised, pathobiological entity that confers a poor prognosis with use of standard intensive chemotherapy. Its early recognition, by use of the gene expression and immunophenotypic criteria outlined here, is essential for the development of an effective clinical management strategy.
  
  
  BACKGROUND
  US National Cancer Institute, Cariplo Foundation, Citta della Speranza Foundation, Italian Association for Cancer Research (AIRC), Italian Ministry for University and Research, and American Lebanese Syrian Associated Charities (ALSAC).
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Coustan-Smith
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.forename: Mihaela
authors.initials: M
authors.lastname: Onciu
authors.forename: Frederick G
authors.initials: FG
authors.lastname: Behm
authors.forename: Susana C
authors.initials: SC
authors.lastname: Raimondi
authors.forename: Deqing
authors.initials: D
authors.lastname: Pei
authors.forename: Cheng
authors.initials: C
authors.lastname: Cheng
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Su
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Rubnitz
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.forename: Andrea
authors.initials: A
authors.lastname: Biondi
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.forename: James R
authors.initials: JR
authors.lastname: Downing
authors.forename: Dario
authors.initials: D
authors.lastname: Campana
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D016130:Immunophenotyping; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male; D020641:Polymorphism, Single Nucleotide; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D012307:Risk Factors