Ikaros Is a Frequently Affected Hematopoietic Differentiation Factor in Pediatric Relapse-Prone Precursor B-Cell Acute Lymphoblastic Leukemia

Relapse is the most common cause of treatment failure in childhood acute lymphoblastic leukemia (ALL), and is difficult to predict in the majority of cases. Here, we performed genome-wide copy number profiling of 34 paired diagnosis-relapse samples from children diagnosed with precursor-B cell ALL. The majority of the copy number abnormalities were preserved between matched diagnosis and relapse samples, but lesions unique in either of the two samples were observed in 82% of the cases. In 68% of the cases lesions present at diagnosis were no longer detected in relapse samples (including recurrent lesions affecting the PAX5, CDKN2A, and EBF genes), indicating that these lesions were secondary events, absent in the original therapy-resistant progenitor clone. Deletions in the IKZF1 gene encoding the hematopoietic differentiation factor Ikaros were observed in 38% of the diagnosis samples, which is >6-fold the amount detected in an unselected group of pediatric ALLs. Tiling-resolution oligo arrays were used to map the breakpoints, which demonstrated that the protein-coding exons 3–6, encoding the DNA-binding Zn-finger domains, were most commonly deleted. Sequence analysis revealed that point mutations in IKZF1 do occur but are less frequent. Furthermore, IKZF1 deletions were always preserved in relapse. Together, we conclude that IKZF1 deletions are frequent events in therapy-resistant clones of relapse-prone pediatric precursor B-ALL.