title: Recurrent deletions of IKZF1 in pediatric acute myeloid leukemia.
abstract: 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.
authors.affiliation: Pediatric Oncology, Erasmus MC-Sophia Children's Hospital Rotterdam, the Netherlands.
authors.forename: Jasmijn D E
authors.initials: JD
authors.lastname: de Rooij
authors.affiliation: Pediatric Oncology, Erasmus MC-Sophia Children's Hospital Rotterdam, the Netherlands.
authors.forename: Eva
authors.initials: E
authors.lastname: Beuling
authors.affiliation: Pediatric Oncology, Erasmus MC-Sophia Children's Hospital Rotterdam, the Netherlands Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
authors.forename: Marry M
authors.initials: MM
authors.lastname: van den Heuvel-Eibrink
authors.affiliation: Pediatric Oncology, Erasmus MC-Sophia Children's Hospital Rotterdam, the Netherlands.
authors.forename: Askar
authors.initials: A
authors.lastname: Obulkasim
authors.affiliation: Hematology, Hopital Saint-Louis, Paris, France.
authors.forename: André
authors.initials: A
authors.lastname: Baruchel
authors.affiliation: Pediatric Hematology/Oncology, 2nd Medical School, Charles University, Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Trka
authors.affiliation: AML-BFM Study Group, Pediatric Hematology/Oncology, Medical School Hannover, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Reinhardt
authors.affiliation: Dutch Childhood Oncology Group (DCOG), The Hague, the Netherlands.
authors.forename: Edwin
authors.initials: E
authors.lastname: Sonneveld
authors.affiliation: Royal Hospital for Sick Children, Glasgow, UK.
authors.forename: Brenda E S
authors.initials: BE
authors.lastname: Gibson
authors.affiliation: Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
authors.affiliation: Pediatric Hematology/Oncology, 2nd Medical School, Charles University, Prague, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Zimmermann
authors.affiliation: Pediatric Oncology, Erasmus MC-Sophia Children's Hospital Rotterdam, the Netherlands.
authors.forename: C Michel
authors.initials: CM
authors.lastname: Zwaan
authors.affiliation: Pediatric Oncology, Erasmus MC-Sophia Children's Hospital Rotterdam, the Netherlands m.fornerod@erasmusmc.nl.
authors.forename: Maarten
authors.initials: M
authors.lastname: Fornerod
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D017353:Gene Deletion; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality*; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics*; D015996:Survival Rate
chemical_list: C497239:IKZF1 protein, human; D009363:Neoplasm Proteins; D051740:Ikaros Transcription Factor