Loss-of-function but not dominant-negative intragenic IKZF1 deletions are associated with an adverse prognosis in adult BCR-ABL-negative acute lymphoblastic leukemia
Benjamin Kobitzsch,
Nicola Gökbuget,
Stefan Schwartz,
Richard Reinhardt,
Monika Brüggemann,
Andreas Viardot,
Ralph Wäsch,
Michael Starck,
Eckhard Thiel,
Dieter Hoelzer,
Thomas Burmeister
Affiliations
Benjamin Kobitzsch
Department of Hematology, Oncology and Tumor Immunology, Charité Universitätsmedizin Berlin, Germany
Nicola Gökbuget
Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt/Main, Germany
Stefan Schwartz
Department of Hematology, Oncology and Tumor Immunology, Charité Universitätsmedizin Berlin, Germany
Richard Reinhardt
Max Planck Genome Center, Köln, Germany
Monika Brüggemann
Department of Hematology, University Hospital Schleswig-Holstein, Kiel, Germany
Andreas Viardot
Department of Medicine III (Hematology, Oncology), Ulm University, Munich, Germany
Ralph Wäsch
Department of Hematology, Oncology and Stem Cell Transplantation, University of Freiburg Medical Center, Munich, Germany
Michael Starck
Department of Hematology, Klinikum München-Schwabing, Munich, Germany
Eckhard Thiel
Department of Hematology, Oncology and Tumor Immunology, Charité Universitätsmedizin Berlin, Germany
Dieter Hoelzer
Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt/Main, Germany
Thomas Burmeister
Department of Hematology, Oncology and Tumor Immunology, Charité Universitätsmedizin Berlin, Germany
Genetic alterations of the transcription factor IKZF1 (“IKAROS”) are detected in around 15–30% of cases of BCR-ABL-negative B-cell precursor acute lymphoblastic leukemia. Different types of intragenic deletions have been observed, resulting in a functionally inactivated allele (“loss-of-function”) or in “dominant-negative” isoforms. The prognostic impact of these alterations especially in adult acute lymphoblastic leukemia is not well defined. We analyzed 482 well-characterized cases of adult BCR-ABL-negative B-precursor acute lymphoblastic leukemia uniformly treated in the framework of the GMALL studies and detected IKZF1 alterations in 128 cases (27%). In 20%, the IKZF1 alteration was present in a large fraction of leukemic cells (“high deletion load”) while in 7% it was detected only in small subclones (“low deletion load”). Some patients showed more than one IKZF1 alteration (8%). Patients exhibiting a loss-of-function isoform with high deletion load had a shorter overall survival (OS at 5 years 28% vs. 59%; P
