WT1 mutations in T-ALL

Tosello, Valeria; Mansour, Marc R.; Barnes, Kelly; Paganin, Maddalena; Sulis, Maria-Luisa; Jenkinson, Sarah; Allen, Christopher G.; Gale, Rosemary E.; Linch, David C.; Palomero, Teresa; Real, Pedro; Vundavalli, Murty V.; Yao, Xiaopan; Richards, Susan M.; Goldstone, Anthony; Rowe, Jacob; Basso, Giuseppe; Wiernik, Peter H.; Paietta, Elisabeth; Pieters, Rob; Horstmann, Martin; Meijerink, Jules P. P.; Ferrando, Adolfo A.

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 ge- netic alterations, but also that relapsed samples frequently lose chromosomal markers present at diagnosis, suggest-ing 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 muta- tions 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 frame- shift 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. Sur- vival analysis demonstrated that WT1 mutations do not confer adverse progno- sis in pediatric and adult T-ALL. Overall, these results identify the presence of WT1 mutations as a recurrent genetic alteration in T-ALL.


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Academic Units
Institute for Cancer Genetics
Pathology and Cell Biology
Published Here
November 27, 2019