title: WT1 mutations in T-ALL.
abstract: The molecular mechanisms involved in disease progression and relapse in T-cell acute lymphoblastic leukemia (T-ALL) are poorly understood. We used single nucleotide polymorphism array analysis to analyze paired diagnostic and relapsed T-ALL samples to identify recurrent genetic alterations in T-ALL. This analysis showed that diagnosis and relapsed cases have common genetic alterations, but also that relapsed samples frequently lose chromosomal markers present at diagnosis, suggesting that relapsed T-ALL emerges from an ancestral clone different from the major leukemic population at diagnosis. In addition, we identified deletions and associated mutations in the WT1 tumor suppressor gene in 2 of 9 samples. Subsequent analysis showed WT1 mutations in 28 of 211 (13.2%) of pediatric and 10 of 85 (11.7%) of adult T-ALL cases. WT1 mutations present in T-ALL are predominantly heterozygous frameshift mutations resulting in truncation of the C-terminal zinc finger domains of this transcription factor. WT1 mutations are most prominently found in T-ALL cases with aberrant rearrangements of the oncogenic TLX1, TLX3, and HOXA transcription factor oncogenes. Survival analysis demonstrated that WT1 mutations do not confer adverse prognosis in pediatric and adult T-ALL. Overall, these results identify the presence of WT1 mutations as a recurrent genetic alteration in T-ALL.
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
authors.forename: Valeria
authors.initials: V
authors.lastname: Tosello
authors.forename: Marc R
authors.initials: MR
authors.lastname: Mansour
authors.forename: Kelly
authors.initials: K
authors.lastname: Barnes
authors.forename: Maddalena
authors.initials: M
authors.lastname: Paganin
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Sulis
authors.forename: Sarah
authors.initials: S
authors.lastname: Jenkinson
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Allen
authors.forename: Rosemary E
authors.initials: RE
authors.lastname: Gale
authors.forename: David C
authors.initials: DC
authors.lastname: Linch
authors.forename: Teresa
authors.initials: T
authors.lastname: Palomero
authors.forename: Pedro
authors.initials: P
authors.lastname: Real
authors.forename: Vundavalli
authors.initials: V
authors.lastname: Murty
authors.forename: Xiaopan
authors.initials: X
authors.lastname: Yao
authors.forename: Susan M
authors.initials: SM
authors.lastname: Richards
authors.forename: Anthony
authors.initials: A
authors.lastname: Goldstone
authors.forename: Jacob
authors.initials: J
authors.lastname: Rowe
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.forename: Peter H
authors.initials: PH
authors.lastname: Wiernik
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Paietta
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
authors.forename: Martin
authors.initials: M
authors.lastname: Horstmann
authors.forename: Jules P P
authors.initials: JP
authors.lastname: Meijerink
authors.forename: Adolfo A
authors.initials: AA
authors.lastname: Ferrando
mesh_terms: D000328:Adult; D002648:Child; D002869:Chromosome Aberrations; D002999:Clone Cells / Q000737:chemistry; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D018450:Disease Progression; D005801:Genes, Homeobox; D016162:Genes, Wilms Tumor; D006801:Humans; D053208:Kaplan-Meier Estimate; D009154:Mutation; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics; D009857:Oncogenes; D020641:Polymorphism, Single Nucleotide; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D012008:Recurrence; D025721:WT1 Proteins / Q000737:chemistry / Q000235:genetics; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D025721:WT1 Proteins