WT1 mutations in T-ALL.
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.
Tosello
Valeria
V
Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
Mansour
Marc R
MR
Barnes
Kelly
K
Paganin
Maddalena
M
Sulis
Maria Luisa
ML
Jenkinson
Sarah
S
Allen
Christopher G
CG
Gale
Rosemary E
RE
Linch
David C
DC
Palomero
Teresa
T
Real
Pedro
P
Murty
Vundavalli
V
Yao
Xiaopan
X
Richards
Susan M
SM
Goldstone
Anthony
A
Rowe
Jacob
J
Basso
Giuseppe
G
Wiernik
Peter H
PH
Paietta
Elisabeth
E
Pieters
Rob
R
Horstmann
Martin
M
Meijerink
Jules P P
JP
Ferrando
Adolfo A
AA
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
D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D025721:WT1 Proteins