Philadelphia-positive B-cell precursor acute lymphoblastic leukemia (Ph+ BCP-ALL) identifies an unfavorable subgroup of pediatric ALL characterized by the presence of the BCR-ABL1 chimeric protein. However, clinically Ph+ BCP-ALL remains a heterogeneous disease with an unfavorable response to therapy in a critical percentage of patients. Even though introduction of tyrosine kinase inhibitors (TKIs) has improved outcome in pediatric Ph− BCP-ALL patients, 30% still relapse or die. 1 Recurrent genomic deletions within the IKAROS (IKZF1) gene locus have been identified in Ph+ BCP-ALL2 and BCP-ALL in general, and recent the work of van der Veer et al. 3 has shown that clinical heterogeneity in response to therapy at least in part may be attributed to the mutation status of IKZF1 in Ph+ BCP-ALL patients. 4, 5

IKAROS is a transcription factor composed of two regions: the C terminal, including two zinc-finger (ZF) domains, that is responsible for the homo–hetero dimerization of the protein, 6 and a N-terminal domain with four ZFs, responsible for the DNA-binding activity: ZF2 and ZF3 ensure a stable DNA-binding, whereas ZF1 and ZF4 regulate the interaction to specific genomic sites. 7, 8 Deletions of IKZF1 can be subdivided into three categories: dominant-negative deletions, characterized by loss of the DNA-binding domain, deletions causing haploinsufficiency that lack the C-terminal dimerization domain and null deletions, that correspond to large chromosome 7 deletions or loss of the ATG codon. 9 Even though the role of IKZF1 deletions as a prognostic factor has been extensively investigated, remaining sometimes controversial, 5 little is known about other genetic alterations at the IKAROS locus. 4, 10 The aim of this study was to assess the incidence of singlenucleotide mutations and in/del in the coding sequence of IKZF1. Leukemic samples of 98 pediatric Ph+ BCP-ALL patients at diagnosis were collected from six European centers that participated in the ‘Ponte di Legno’(pre-TKI) cohort11 study and