Tumor suppressors BTG1 and IKZF1 cooperate during mouse leukemia development and increase relapse risk in B-cell precursor acute lymphoblastic leukemia patients
Blanca Scheijen,
Judith M. Boer,
René Marke,
Esther Tijchon,
Dorette van Ingen Schenau,
Esmé Waanders,
Liesbeth van Emst,
Laurens T. van der Meer,
Rob Pieters,
Gabriele Escherich,
Martin A. Horstmann,
Edwin Sonneveld,
Nicola Venn,
Rosemary Sutton,
Luciano Dalla-Pozza,
Roland P. Kuiper,
Peter M. Hoogerbrugge,
Monique L. den Boer,
Frank N. van Leeuwen
Affiliations
Blanca Scheijen
Laboratory of Pediatric Oncology, Radboud university medical center, Nijmegen, the Netherlands
Judith M. Boer
Department of Pediatric Oncology, Erasmus MC-Sophia Children’s Hospital, Erasmus University Medical Center, Rotterdam, the Netherlands
René Marke
Laboratory of Pediatric Oncology, Radboud university medical center, Nijmegen, the Netherlands
Esther Tijchon
Laboratory of Pediatric Oncology, Radboud university medical center, Nijmegen, the Netherlands
Dorette van Ingen Schenau
Laboratory of Pediatric Oncology, Radboud university medical center, Nijmegen, the Netherlands
Esmé Waanders
Department of Human Genetics, Radboud university medical center, Nijmegen, the Netherlands;Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
Liesbeth van Emst
Laboratory of Pediatric Oncology, Radboud university medical center, Nijmegen, the Netherlands
Laurens T. van der Meer
Laboratory of Pediatric Oncology, Radboud university medical center, Nijmegen, the Netherlands
Rob Pieters
Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
Gabriele Escherich
Research Institute Children’s Cancer Center and Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Martin A. Horstmann
Research Institute Children’s Cancer Center and Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Edwin Sonneveld
Dutch Childhood Oncology Group, The Hague, the Netherlands
Nicola Venn
Australian and New Zealand Children’s Oncology Group, Children’s Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia
Rosemary Sutton
Australian and New Zealand Children’s Oncology Group, Children’s Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia
Luciano Dalla-Pozza
Oncology Unit, The Children’s Hospital at Westmead, Sydney, Australia
Roland P. Kuiper
Department of Human Genetics, Radboud university medical center, Nijmegen, the Netherlands;Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
Peter M. Hoogerbrugge
Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
Monique L. den Boer
Department of Pediatric Oncology, Erasmus MC-Sophia Children’s Hospital, Erasmus University Medical Center, Rotterdam, the Netherlands
Frank N. van Leeuwen
Laboratory of Pediatric Oncology, Radboud university medical center, Nijmegen, the Netherlands
Deletions and mutations affecting lymphoid transcription factor IKZF1 (IKAROS) are associated with an increased relapse risk and poor outcome in B-cell precursor acute lymphoblastic leukemia. However, additional genetic events may either enhance or negate the effects of IKZF1 deletions on prognosis. In a large discovery cohort of 533 childhood B-cell precursor acute lymphoblastic leukemia patients, we observed that single-copy losses of BTG1 were significantly enriched in IKZF1-deleted B-cell precursor acute lymphoblastic leukemia (P=0.007). While BTG1 deletions alone had no impact on prognosis, the combined presence of BTG1 and IKZF1 deletions was associated with a significantly lower 5-year event-free survival (P=0.0003) and a higher 5-year cumulative incidence of relapse (P=0.005), when compared with IKZF1-deleted cases without BTG1 aberrations. In contrast, other copy number losses commonly observed in B-cell precursor acute lymphoblastic leukemia, such as CDKN2A/B, PAX5, EBF1 or RB1, did not affect the outcome of IKZF1-deleted acute lymphoblastic leukemia patients. To establish whether the combined loss of IKZF1 and BTG1 function cooperate in leukemogenesis, Btg1-deficient mice were crossed onto an Ikzf1 heterozygous background. We observed that loss of Btg1 increased the tumor incidence of Ikzf1+/− mice in a dose-dependent manner. Moreover, murine B cells deficient for Btg1 and Ikzf1+/− displayed increased resistance to glucocorticoids, but not to other chemotherapeutic drugs. Together, our results identify BTG1 as a tumor suppressor in leukemia that, when deleted, strongly enhances the risk of relapse in IKZF1-deleted B-cell precursor acute lymphoblastic leukemia, and augments the glucocorticoid resistance phenotype mediated by the loss of IKZF1 function.
