The SET-NUP214 (TAF1/CAN) fusion gene resulting from either cryptic t(9;9)(q34;q34) or del(9)(q34.11q34.13)is a rare genetic event in T-cell acute lymphoblastic leukemia (T-ALL). Eleven of 196 (6%) T-ALLs enrolled in the French GRAALL-2003 and -2005 trials harbored a SET-NUP214 transcript. SET-NUP214 positive patients were predominantly (10/11; 91%) T-cell receptor (TCR) negative and strikingly associated to TCRγδ lineage T-ALLs, as defined by expression of a TCRγδ, or TCRδ and/or TCRγ rearrangements but no complete TCRβ VDJ rearrangement in surface CD3/TCR negative cases. When compared to SET-NUP214 negative patients, SET-NUP214+ cases showed a significantly higher rate of corticosteroid resistance (91% versus 44%; p=0.003) and chemoresistance (100% versus 44%; p=0.0001). All but one SET-NUP214+ patients achieved complete remission and nine were allografted. Despite the poor early treatment sensitivity, the outcome of SET-NUP214+ patients was similar to that of SET-NUP214-cases (p=0.52 for event-free survival and p=0.86 for overall survival). This trial is registered at clinicaltrials.gov, identifier: NCT00327678.