Recurrent deletions of IKZF1 in pediatric acute myeloid leukemia

• Published in: Haematologica (Roma) Vol. 100; no. 9; pp. 1151 - 1159
• Main Authors: de Rooij, Jasmijn D E, Beuling, Eva, van den Heuvel-Eibrink, Marry M, Obulkasim, Askar, Baruchel, André, Trka, Jan, Reinhardt, Dirk, Sonneveld, Edwin, Gibson, Brenda E S, Pieters, Rob, Zimmermann, Martin, Zwaan, C Michel, Fornerod, Maarten
• Format: Journal Article
• Language: English
• Published: Italy Ferrata Storti Foundation 01.09.2015
• Subjects: Adolescent; Child; Child, Preschool; Chromosome Deletion; Chromosomes, Human, Pair 7 - genetics; Disease-Free Survival; Female; Gene Deletion; Humans; Ikaros Transcription Factor - genetics; Infant; Infant, Newborn; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - mortality; Male; Neoplasm Proteins - genetics; Survival Rate
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2015.124321

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.