The IKAROS/COBL connection

We have investigated patients with Ikaros deletions (IKZF1Δ) at 7p12. IKZF1Δ mutations are correlated with a differentiation block in normal B-cell devlopment and frequently diagnosed in preB cell ALL and BCR-ABL+ ALL leukemia patients. Here, we focussed on the analysis of patients with whole gene deletions of IKZF1. Our preliminary results demonstrated that all these deletion started within intron 5 of the COBL gene. Additionally, IKZF1-COBL fusions were recurrently identified in different leukemia patients (n = 2). While breakpoints are clustering in the already described hotspot of Ikaros, all deletions cluster within intron 5 of COBL. Moreover, we identified also patients that displayed chromosomal translocations of COBL to other chromosomes (n = 2). This would indicate that the genetic hotspot is residing with COBL, and not within the IKZF1 gene. Genetic hostpots in general display chromosomal translocations, deletions, duplications and inversions. We have already identified chromosomal translocations, deletions up to 800 KB and ending inside of IKZF1 and inversions of COBL gene portions. ll this points to a mechanism on how IKZF1Δ may occur.