IKAROS family zinc finger 1/IKZF1 is a transcription factor important in lymphoid differentiation, and a known tumor suppressor in acute lymphoid leukemia. Recent studies suggest that IKZF1 is also involved in myeloid differentiation. To investigate whether IKZF1 deletions also play a role in pediatric acute myeloid leukemia, we screened a panel of pediatric acute myeloid leukemia samples for deletions of the IKZF1 locus using multiplex ligation-dependent probe amplification and for mutations using direct sequencing. Three patients were identified with a single amino acid variant without change of IKZF1 length. No frame-shift mutations were found. Out of 11 patients with an IKZF1 deletion, 8 samples revealed a complete loss of chromosome 7, and 3 cases a focal deletion of 0.1-0.9Mb. These deletions included the complete IKZF1 gene (n=2) or exons 1-4 (n=1), all leading to a loss of IKZF1 function. Interestingly, differentially expressed genes in monosomy 7 cases (n=8) when compared to non-deleted samples (n=247) significantly correlated with gene expression changes in focal IKZF1-deleted cases (n=3). Genes with increased expression included genes involved in myeloid cell self-renewal and cell cycle, and a significant portion of GATA target genes and GATA factors. Together, these results suggest that loss of IKZF1 is recurrent in pediatric acute myeloid leukemia and might be a determinant of oncogenesis in acute myeloid leukemia with monosomy 7.

AML BFM Study Group Pediatric Hematology Oncology Medical School Hannover Germany

Dutch Childhood Oncology Group The Hague the Netherlands

Hematology Hopital Saint Louis Paris France

Pediatric Hematology Oncology 2nd Medical School Charles University Prague Czech Republic

Pediatric Oncology Erasmus MC Sophia Children's Hospital Rotterdam the Netherlands

Pediatric Oncology Erasmus MC Sophia Children's Hospital Rotterdam the Netherlands Princess Máxima Center for Pediatric Oncology Utrecht the Netherlands

Princess Máxima Center for Pediatric Oncology Utrecht the Netherlands

Royal Hospital for Sick Children Glasgow UK

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Mutated IKZF1 is an independent marker of adverse risk in acute myeloid leukemia