Overexpression of dominant-negative Ikaros 6 isoform is associated with resistance to TKIs in patients with Philadelphia chromosome positive acute lymphoblastic leukemia.

The clinical significance of the dominant-negative Ikaros 6 (DN-IK6) in the treatment of patients with Philadelphia-positive acute lymphoblastic leukemia (Ph+-ALL) with tyrosine kinase inhibitors (TKIs) remains elusive. In the present study, it was demonstrated that DN-IK6 was overexpressed in B-cell (B)-ALL cases compared with T cell-ALL cases at the mRNA and protein levels. Furthermore, nucleotide sequencing revealed that DN-IK6 was due to the deletion of IKAROS family zinc finger 1 exons 4-7. The outcome of patients with Ph+-B-ALL with DN-IK6, and treated with TKIs and hyper-cyclophosphamide/vincristine/doxorubicin/dexamethasone regimen were restrospectively evaluated in a 2 year follow-up. The results demonstrated that those with the DN isoform exhibited significantly lower incidences of remission, shorter median cumulative incidence of relapse times (P<0.05) and shorter median overall survival times (P<0.05) compared with those without the DN isoform. In conclusion, the results of the present study demonstrated that DN-IK6 is overexpressed in the majority of patients with Ph+-ALL, and is significantly associated with resistance to TKI therapy.