Deletions in IKZF1 are found in ~15% of children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). There is strong evidence for the poor prognosis of IKZF1 deletions affecting exons 4-7 and exons 1-8, but evidence for the remaining 33% of cases harboring other variants of IKZF1 deletions is lacking. In an international multicenter study we analyzed the prognostic value of these rare variants in a case-control design. Each IKZF1-deleted case was matched to three IKZF1 wild-type controls based on cytogenetic subtype, treatment protocol, risk stratification arm, white blood cell count and age. Hazard ratios for the prognostic impact of rare IKZF1 deletions on event-free survival were calculated by matched pair Cox regression. Matched pair analysis for all 134 cases with rare IKZF1 deletions together revealed a poor prognosis (P<0.001) that was evident in each risk stratification arm. Rare variant types with the most unfavorable event-free survival were DEL 2-7 (P=0.03), DEL 2-8 (P=0.002) and DEL-Other (P<0.001). The prognosis of each type of rare variant was equal or worse compared with the well-known major DEL 4-7 and DEL 1-8 IKZF1 deletion variants. We therefore conclude that all variants of rare IKZF1 deletions are associated with an unfavorable prognosis in pediatric BCP-ALL.

AIEOP Associazione Italiana Ematologia Oncologia Pediatrica University of Milano Bicocca Monza Italy

ANZCHOG Australian and New Zealand Children's Oncology Group Children's Cancer Institute Australia Lowy Cancer Research Centre UNSW Sydney Australia

BFM A Berlin Frankfurt Münster Austria Study Group Department of Pediatric Hematology and Oncology St Anna Children's Hospital Department of Pediatrics and Adolescent Medicine Medical University of Vienna Vienna Austria

BFM G Berlin Frankfurt Münster Germany Study Group University of Schleswig Holstein Kiel Germany

Children's Cancer Research Institute St Anna Kinderkrebsforschung Vienna Austria

CLIP Childhood Leukaemia Investigation Prague 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

COALL Study Group Research Centre and Clinic for Pediatric Oncology University Medical Centre Eppendorf Hamburg Germany

DCOG Dutch Childhood Oncology Group the Hague The Netherlands

Department of Biostatistics Erasmus MC Rotterdam The Netherlands

Department of Haematology Sheffield Children's Hospital Sheffield UK

Department of Human Genetics Radboud University Medical Center and Radboud Institute for Molecular Life Sciences Nijmegen The Netherlands

Department of Medical Statistics and Bioinformatics Leiden University Medical Centre Leiden The Netherlands

Department of Pediatric Oncology Erasmus MC Sophia Children's Hospital Rotterdam The Netherlands

Leukaemia Research Cytogenetics Group Northern Institute for Cancer Research Newcastle University Newcastle upon Tyne UK

Pediatric Haematology and Oncology Program Research Centre Instituto Nacional de Câncer Rio de Janeiro Brazil

Pediatric Hematology and Oncology Hannover Medical School Hannover Germany

PPLLSG Polish Pediatric Leukaemia Lymphoma Study Group Department of Pediatric Hematology and Oncology Medical University of Silesia Zabrze Poland

PPLLSG Polish Pediatric Leukaemia Lymphoma Study Group Department of Pediatrics Oncology Haematology and Diabetology Medical University of Lodz Lodz Poland

Princess Máxima Center for Pediatric Oncology Utrecht The Netherlands

Zobrazit více v PubMed

Int J Oncol. 2012 Jan;40(1):53-62 PubMed

Leukemia. 2010 Jul;24(7):1258-64 PubMed

Nat Genet. 2014 Feb;46(2):116-25 PubMed

Haematologica. 2013 Aug;98(8):1226-31 PubMed

Leukemia. 2014 Jan;28(1):70-7 PubMed

Haematologica. 2013 Dec;98(12):e164-5 PubMed

Nat Immunol. 2014 Mar;15(3):294-304 PubMed

Blood. 2013 Oct 10;122(15):2622-9 PubMed

Blood. 2009 Sep 3;114(10):2159-67 PubMed

Nature. 2008 May 1;453(7191):110-4 PubMed

Nat Immunol. 2014 Mar;15(3):283-93 PubMed

EMBO J. 2003 May 1;22(9):2211-23 PubMed

Eur J Haematol. 2013 Sep;91(3):201-8 PubMed

Pediatr Blood Cancer. 2013 Mar;60(3):420-7 PubMed

Blood. 2014 Mar 13;123(11):1691-8 PubMed

Blood. 2013 Mar 7;121(10):1769-82 PubMed

Nat Immunol. 2013 Oct;14(10):1073-83 PubMed

J Immunol. 2001 Aug 15;167(4):1867-70 PubMed

Haematologica. 2013 Mar;98(3):428-32 PubMed

Leukemia. 2010 Feb;24(2):265-84 PubMed

Haematologica. 2013 Apr;98(4):597-601 PubMed

Leukemia. 2013 Nov;27(11):2256-9 PubMed

Leukemia. 2013 Feb;27(2):503-7 PubMed

Blood. 2013 Oct 31;122(18):3149-59 PubMed

Oncogene. 2006 Feb 16;25(7):1118-24 PubMed

N Engl J Med. 2006 Jan 12;354(2):166-78 PubMed

Leukemia. 2002 Jul;16(7):1285-92 PubMed

Genes Chromosomes Cancer. 2015 May;54(5):315-25 PubMed

Mol Cell Biol. 2013 Aug;33(16):3064-76 PubMed

Leukemia. 2012 Jul;26(7):1507-16 PubMed

N Engl J Med. 2009 Jan 29;360(5):470-80 PubMed

Int J Hematol. 2014 Sep;100(3):220-9 PubMed

EMBO J. 1996 Oct 1;15(19):5358-69 PubMed

Cancer Sci. 2011 Oct;102(10):1874-81 PubMed

Leukemia. 2011 Feb;25(2):254-8 PubMed

Leukemia. 2014 Jan;28(1):182-5 PubMed

Br J Haematol. 2015 Sep;170(6):847-58 PubMed

Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):680-5 PubMed

Leukemia. 2013 Jul;27(7):1497-503 PubMed

Stem Cells. 2009 Dec;27(12 ):3082-92 PubMed

Leukemia. 2015 Nov;29(11):2154-61 PubMed

Cell. 1994 Oct 7;79(1):143-56 PubMed

Overt and covert genetic causes of pediatric acute lymphoblastic leukemia

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

Measurable residual disease analysis in paediatric acute lymphoblastic leukaemia patients with ABL-class fusions

Genomic landscape of pediatric B-other acute lymphoblastic leukemia in a consecutive European cohort